Literature Reviews

Procedure-specific systematic review summary

Bibliography

Abdominal Hysterectomy

Nelskyla et al 1997

Recovery and outcome after propofol and isoflurane anesthesia in patients undergoing laparoscopic hysterectomy.

Nelskyla K, Eriksson H, Soikkeli A, Korttila K.

Acta Anaesthesiol Scand 1997;41(3):360–363.

BACKGROUND: Laparoscopic hysterectomy (LH) is expected to provide fast and comfortable recovery, plus an early return to normal daily activities. This study was carried out to compare the outcome after LH in patients anesthetized with isoflurane or propofol. METHODS: Sixty-two patients undergoing LH were randomized to receive either isoflurane-N2O or propofol-N2O anesthesia. The times when the patients could drink, void and walk were recorded. Recovery was also evaluated by the Digit Symbol Substitution Test in the postanesthesia care unit (PACU) 60 and 120 min after the operation. The patients were also given a questionnaire on their further recovery (return to daily activities, pain and nausea) to be filled out at home. RESULTS: Early recovery was significantly (p < 0.05) faster in the isoflurane group (eye opening within 3 min, orientation in 6 min) when compared to the propofol group (eye opening within 7 min, orientation in 14 min), but there was no significant difference in the other parameters of recovery. Most of the patients were discharged from the hospital on the first postoperative day in both groups. Twenty-five percent of the patients, however, stayed two nights in hospital, mainly for social reasons. No difference was found regarding the recovery at home: the patients resumed their normal daily activities on about the sixth postoperative day (median). CONCLUSIONS: It is concluded that both isoflurane and propofol are suitable anesthetics for LH. In this study recovery was not fast enough to make the patients suitable for same-day surgery.

Turan et al 2004

The analgesic effects of gabapentin after total abdominal hysterectomy

Turan A, Karamanlioglu B, Memis D, Usar P, Pamukçu Z, Türe M

Anesthesia and analgesia 2004;98(5):1370-3

We investigated, in a randomized, placebo-controlled, double-blind study, the efficacy and safety of gabapentin on pain after abdominal hysterectomy and on tramadol consumption in patients. The 50 patients were randomized to receive either oral placebo or gabapentin 1200 mg 1 h before surgery. Anesthesia was induced with propofol and maintained with sevoflurane in 50% N(2)O/O(2) with a fresh gas flow of 2 L/min (50% N(2)O in O(2)) and fentanyl (2 microg/kg). All patients received patient-controlled analgesia with tramadol with a 50 mg initial loading dose, 20 mg incremental dose, 10-min lockout interval, and 4-h limit of 300 mg. The incremental dose was increased to 30 lower in the gabapentin group when compared with the placebo group up to 20 h after surgery. The tramadol consumption at 12, 16, 20, and 24 h and total tramadol consumption were significantly less in the gabapentin group when compared with placebo group. Sedation scores were similar at all the measured times. There were no differences between groups in adverse effects. Preoperative oral gabapentin decreased mg if analgesia was inadequate after 1 h. Patients were studied at 4, 8, 12, 16, 20, and 24 h for visual analog (VAS) pain scores, heart rate, peripheral oxygen saturation, mean arterial blood pressure, respiratory rate, sedation, and tramadol consumption. The VAS scores in the sitting and supine position at 1, 4, 8, 12, 16, and 20 h were significantly pain scores and postoperative tramadol consumption in patients after abdominal hysterectomy. IMPLICATIONS: This randomized, controlled trial examined the effects of preoperative oral gabapentin 1200 mg on postoperative pain and tramadol consumptions. We conclude that preoperative oral gabapentin is effective in reducing postoperative pain scores and tramadol consumption in patients after abdominal hysterectomy.

Gilron et al 2005

A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy.

Gilron I, Orr E, Tu D, O'Neill JP, Zamora JE, Bell AC.

Pain 2005;113(1-2):191–200.

Current treatments for post-injury movement-evoked pain are inadequate. Non-opioids may complement opioids, which preferentially reduce spontaneous pain, but most have incomplete efficacy as single agents. This trial evaluates efficacy of a gabapentin-rofecoxib combination following hysterectomy. In addition to IV-PCA morphine, 110 patients received either placebo, gabapentin (1800 mg/day), rofecoxib (50 mg/day) or a gabapentin-rofecoxib combination (1800/50 mg/day) starting 1 h pre-operatively for 72 h. Outcomes included pain at rest, evoked by sitting, peak expiration and cough, morphine consumption and peak expiratory flow (PEF). For placebo, gabapentin, rofecoxib and combination, 24 h pain (100 mm VAS) was: at rest-23.6 (P<0.05 vs. all treatments), 13.8, 14.4 and 12.1; during cough-50.7 (P<0.05 vs. all treatments), 41.5, 44.8 and 30.8; 48 h morphine consumption (mg) was: 130.4 (P<0.05 vs. all treatments), 81.7, 75.6 and 57.2 (P<0.05 vs. gabapentin and rofecoxib) and 48 h PEF (% baseline) was: 63.9 (P<0.05 vs. all treatments), 77.2, 76.7 and 87.5 (P<0.05 vs. gabapentin and rofecoxib). Adverse effects were similar in all groups except sedation which was more frequent with gabapentin. Combination and rofecoxib reduced pain interference with movement, mood and sleep (P<0.05) and combination was superior to gabapentin for all these three (P<0.05). These data suggest that a gabapentin-rofecoxib combination is superior to either single agent for postoperative pain. Other benefits include opioid sparing, reduced interference with movement, mood and sleep and increased PEF suggesting accelerated pulmonary recovery. Future research should identify optimal dose-ratios for this and other analgesic combinations.

Gilron et al 2005

A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy

Gilron I, Orr E, Tu D, O'Neill JP, Zamora JE, Bell AC

Pain 2005; 113(1-2):191-200

Current treatments for post-injury movement-evoked pain are inadequate. Non-opioids may complement opioids, which preferentially reduce spontaneous pain, but most have incomplete efficacy as single agents. This trial evaluates efficacy of a gabapentin-rofecoxib combination following hysterectomy. In addition to IV-PCA morphine, 110 patients received either placebo, gabapentin (1800 mg/day), rofecoxib (50 mg/day) or a gabapentin-rofecoxib combination (1800/50 mg/day) starting 1 h pre-operatively for 72 h. Outcomes included pain at rest, evoked by sitting, peak expiration and cough, morphine consumption and peak expiratory flow (PEF). For placebo, gabapentin, rofecoxib and combination, 24 h pain (100 mm VAS) was: at rest-23.6 (P<0.05 vs. all treatments), 13.8, 14.4 and 12.1; during cough-50.7 (P<0.05 vs. all treatments), 41.5, 44.8 and 30.8; 48 h morphine consumption (mg) was: 130.4 (P<0.05 vs. all treatments), 81.7, 75.6 and 57.2 (P<0.05 vs. gabapentin and rofecoxib) and 48 h PEF (% baseline) was: 63.9 (P<0.05 vs. all treatments), 77.2, 76.7 and 87.5 (P<0.05 vs. gabapentin and rofecoxib). Adverse effects were similar in all groups except sedation which was more frequent with gabapentin. Combination and rofecoxib reduced pain interference with movement, mood and sleep (P<0.05) and combination was superior to gabapentin for all these three (P<0.05). These data suggest that a gabapentin- rofecoxib combination is superior to either single agent for postoperative pain. Other benefits include opioid sparing, reduced interference with movement, mood and sleep and increased PEF suggesting accelerated pulmonary recovery. Future research should identify optimal dose-ratios for this and other analgesic combinations.

Dierking et al 2004

Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial.

BACKGROUND: Preliminary clinical studies have suggested that gabapentin may produce analgesia and reduce the need for opioids in postoperative patients. The aim of the present study was to investigate the opioid-sparing and analgesic effects of gabapentin administered during the first 24 h after abdominal hysterectomy. METHODS: In a randomized, double-blind study, 80 patients received oral gabapentin 1200 mg or placebo 1 h before surgery, followed by oral gabapentin 600 mg or placebo 8, 16 and 24 h after the initial dose. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 24 h postoperatively. Pain was assessed on a visual analogue scale (VAS) at rest and during mobilization, nausea, somnolence and dizziness on a four-point verbal scale, and vomiting as present/not present at 2, 4, 22 and 24 h postoperatively. RESULTS: Thirty-nine patients in the gabapentin group and 32 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from median 63 (interquartile range 53-88) mg to 43 (28-60) mg (P < 0.001). We observed a significant inverse association between plasma levels of gabapentin at 2 h postoperatively, and morphine usage from 0 to 2 h, and from 0 to 4 h postoperatively (R2 = 0.30, P = 0.003 and R2 = 0.24 P = 0.008, respectively). No significant differences in pain at rest or during mobilization, or in side-effects, were observed between groups. CONCLUSION: Gabapentin in a total dose of 3000 mg, administered before and during the first 24 h after abdominal hysterectomy, reduced morphine consumption with 32%, without significant effects on pain scores. No significant differences in side-effects were observed between study-groups.

Turan et al 2006

Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management

The cyclooxygenase-2 inhibitor, rofecoxib, was a popular analgesic adjuvant for improving perioperative pain management. We designed this placebo-controlled study to test the hypothesis that gabapentin could produce similar reductions in postoperative pain and opioid analgesic usage, thereby improving the recovery process. One hundred patients undergoing abdominal hysterectomy procedures were randomly assigned to one of four treatment groups: 1) control group received placebo capsules and pills before and for 2 days after surgery, 2) rofecoxib group received 50 mg/d PO and placebo capsules before and after surgery and, 3) gabapentin group received 1.2 g/d PO and placebo pills before and after surgery, and 4) combination group received rofecoxib 50 mg/d and gabapentin 1.2 g/d PO before and after surgery. The anesthetic technique was standardized and the postoperative assessments included verbal rating scales for pain and sedation, IV morphine usage, quality of recovery assessment, recovery of bowel function, resumption of normal activities, and patient satisfaction with their pain management. Postoperative pain scores were significantly reduced in all three analgesic treatment groups (versus control group). Compared with the control group, patient-controlled analgesia morphine usage was also significantly reduced in the 3 analgesic treatment groups at 1, 8, 24, and 30 h after surgery. Total PCA morphine usage was decreased by 43%, 24%, and 50% in groups 2, 3, and 4, respectively, compared with group 1. Oral analgesic consumption was also smaller in groups 2 and 4 when compared with the control group. The opioid-sparing effects of rofecoxib and gabapentin lead to a faster recovery of bowel function. Discharge eligibility scores in groups 2 and 4 were improved at 24 h when compared with group 1, and patient satisfaction with postoperative pain management was significantly higher at 24 h in all 3 analgesic treatment groups. At the 72 h follow-up, all of the patients in group 4 were completely satisfied with their pain management compared with only 32%, 64%, and 72% in groups 1, 2, and 3, respectively. Gabapentin (1.2 g/d PO) appears to be an acceptable alternative to rofecoxib (50 mg/d PO) for short-term use as an adjuvant to opioid analgesics in patients undergoing lower abdominal surgery.

Dahl et al 2004

'Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain.

Dahl JB, Mathiesen O, Moiniche S.

Acta Anaesthesiol Scand 2004;48:1130–1136.

Substantial progress has been made during the last decades in our understanding of acute pain mechanisms, and this knowledge has encouraged the search for novel treatments. Of particular interest has been the observation that tissue injury initiates a number of modulations of both the peripheral and the central pain pathways, which convert the system from a 'physiological' to a 'pathological' mode of processing afferent information. Gabapentin, which binds to the alpha(2)delta subunit of the voltage-dependent calcium channel, is active in animal models of 'pathological' but not in models of 'physiological' pain. Consequently, attention has so far been focused on neuropathic pain as a target for the clinical use of gabapentin and analogues. Recently, several reports have indicated that gabapentin may have a place in the treatment of post-operative pain. This article presents a brief summary of the potential mechanisms of post-operative pain, and a systematic review of the available data of gabapentin and pregabalin for post-operative analgesia. It is concluded that the results with gabapentin and pregabalin in post-operative pain treatment published so far are promising. It is suggested that future studies should explore the effects of 'protective premedication' with combinations of various antihyperanalgesic and analgesic drugs for post-operative analgesia.

Ho et al 2006

The objective of this systematic review was to evaluate the efficacy and tolerability of perioperative gabapentin administration for the control of acute postoperative pain. We searched Medline (1966-2006), the Cochrane Library (2006), Scopus, CINAHL and bibliographies from clinical trials and review articles. We included randomized controlled trials (RCTs) comparing gabapentin with inactive controls in surgical patients. Sixteen valid RCTs were included. Weighted mean difference (WMD) for postoperative pain intensity (0-100 mm visual analogue scale) was -16.55 mm at 6 h and -10.87 mm at 24 h for treatment with a single preoperative dose of gabapentin 1200 mg. Cumulative opioid consumption at 24 h was also significantly decreased with gabapentin (WMD, -27.90 mg). When gabapentin was administered at doses less than 1200 mg, pain intensity was also lower at 6 h (WMD, -22.43 mm) and 24 h (WMD, -13.18 mm). Cumulative 24 h opioid consumption was also lower (WMD, -7.25 mg). Gabapentin was associated with an increased risk of sedation (Peto OR 3.86; 95% CI 2.50-5.94) but less opioid-related side effects such as vomiting (Peto OR 0.58; 95% CI 0.39-0.86) and pruritus (Peto OR 0.27; 95% CI 0.10-0.74). In conclusion, gabapentin has an analgesic and opioid-sparing effect in acute postoperative pain management when used in conjunction with opioids.

Ng et al 2003

Analgesic effects of parecoxib following total abdominal hysterectomy.

Ng A, Smith G, Davidson AC.

Br J Anaesth 2003;90(6):746–749.

BACKGROUND: Forty-eight ASA I-II patients undergoing total abdominal hysterectomy (TAH) were studied in a double blind, randomized placebo controlled trial of parecoxib for postoperative analgesia. METHODS: All patients were given propofol 2-4 mg kg(-1) i.v., a non-depolarizing muscle relaxant, morphine 10 mg i.v. and prochlorperazine 12.5 mg i.m. intraoperatively. Their lungs were ventilated with nitrous oxide and isoflurane 1-1.5% in oxygen. Morphine was self-administered for postoperative analgesia via a patient controlled analgesia (PCA) device. Patients were allocated randomly to receive either parecoxib 40 mg i.v. or normal saline on induction of anaesthesia. RESULTS: Twelve patients did not complete the study. Of the remaining 36 patients, there was no significant difference between the treatment groups in age, weight, ASA status, duration of surgery, or intraoperative dose of morphine. However, mean (95% CI) 24 h morphine consumption of 54 (42-65) mg in the parecoxib group was significantly (P=0.04) lower than that of 72 (58-86) mg in the placebo group. Pain intensity scores on sitting up were significantly lower (P=0.02) in the parecoxib group compared with placebo. There was no significant difference between the treatment groups in pain intensity scores at rest and on deep inspiration, or in nausea, total number of vomiting episodes, median number of rescue antiemetic doses, and sedation scores. CONCLUSIONS: Parecoxib 40 mg i.v. may be recommended in patients having TAH as it provides morphine-sparing analgesia.

Celik et al 2003

A comparative study of the effect of rofecoxib (a COX 2 inhibitor) and naproxen sodium on analgesic requirements after abdominal hysterectomy.

Celik JB, Tuncer S, Reisli R, Sarkilar G, Celik C, Akyurek C.

Arch Gynecol Obstet 2003;268(4):297.

This study evaluated the analgesic efficacy of administering preoperatively rofecoxib or naproxen sodium to patients undergoing abdominal hysterectomy. A randomized, double-blinded prospective study was conducted with 60 women undergoing elective abdominal hysterectomy under general anesthesia. Patients were randomly allocated into one of three equally sized groups. Patients in the first group received rofecoxib 50 mg 1 h before operation (group R), patient in the second group received naproxen sodium 550 mg 1 h before surgery (group N) and patients in the third group received a placebo tablet in the same time (group P). Total amount of used morphine mixture was higher in placebo group (93+/-6 ml) than in the group R (50+/-4 ml) and group N (64+/-6 ml). There were significant difference for total amount of used morphine mixture between group P and other two groups. There was significant difference in the volumes of morphine mixture used in the first 12 h in group P and other two groups. The occurrence of side effects such as, dyspepsia, epigastric discomfort, heartburn, were similar in group R and group P. However, this side effects were increased in group N. Rofecoxib receiving preoperatively was provided clinical efficacy for postoperative pain control and well tolerated for gastrointestinal side effects comparable with naproxen sodium.

Hegi et al 2004

Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac.

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors or non-steroidal anti- inflammatory drugs (NSAIDs) are frequently omitted for perioperative pain relief because of potential side-effects. COX-2-selective inhibitors may have a more favourable side-effect profile. This study tested the hypothesis that the COX-2-selective inhibitor rofecoxib has less influence on platelet function than the NSAID diclofenac in gynaecological surgery. In addition, analgesic efficacy and side-effects of the two drugs were compared. METHODS: In this single-centre, prospective, double-blind, active controlled study, women undergoing vaginal hysterectomy (n = 25) or breast surgery (n = 25) under general anaesthesia received preoperatively 50 mg of rofecoxib p.o. followed 8 and 16 h later by two doses of placebo or three doses of diclofenac 50 mg p.o. at the same time points. We assessed arachidonic acid-stimulated platelet aggregation before and 4 h after the first dose of study medication, estimated intraoperative blood loss, and haemoglobin loss until the first morning after surgery. Analgesic efficacy, use of rescue analgesics, and side-effects were also recorded. RESULTS: In the rofecoxib group, stimulated platelet aggregation was disturbed less (p = 0.02), and estimated intraoperative blood loss (p = 0.01) and the decrease in haemoglobin were lower (p = 0.01). At similar pain ratings, the use of anti-emetic drugs was less in the rofecoxib group (p = 0.03). CONCLUSION: Besides having a smaller effect on platelet aggregation, one oral dose of rofecoxib 50 mg given before surgery provided postoperative analgesia similar to that given by three doses of diclofenac 50 mg and was associated with less use of anti-emetics and less surgical blood loss in gynaecological surgery compared with diclofenac.

BACKGROUND: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. OBJECTIVE: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. RESULTS: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. CONCLUSION: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

Greenberg et al 2000

A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers.

The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n=12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37oC. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 µg/ml collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.

BACKGROUND: Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance. OBJECTIVE: To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients. METHOD: Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions. RESULTS: Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs. CONCLUSION: This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.

Nussmeier et al 2005

Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.

Background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a randomized trial to assess the safety of these drugs after CABG. Methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications. Results As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4% in each of these two groups vs. 4.0% in the placebo group; risk ratio for each comparison, 1.9; 95% confidence interval, 1.1 to 3.2; p = 0.02 for each comparison with the placebo group). In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0% vs. 0.5%; risk ratio, 3.7; 95% confidence interval, 1.0 to 13.5; p = 0.03). Conclusions The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances.

EMEA 2004a

Committee for Medicinal Products for Human Use, European Public Assessment Report (EPAR): Bextra.

EMEA.

Available at http://www.emea.eu.int/humandocs/Humans/EPAR/bextra/bextra.htm

O'Connor et al 2003

Hepatocellular damage from non-steroidal anti-inflammatory drugs.

O'Connor N, Dargan PI, Jones AL.

QJM 2003;96(11):787–791.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of rheumatological disorders, and as analgesics and antipyretics. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with all NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within 4-6 weeks of stopping the causative drug. However, some patients may develop acute liver failure and successful orthotopic liver transplantation may be undertaken in such patients. Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria, and to production of active metabolites, particularly n,5-dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial permeability transition (MPT) has also been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling and oxidation of NADP and protein thiols. Physicians and hepatologists must be vigilant to the hepatotoxic potential of any NSAID, as increased awareness, surveillance and reporting of these events will lead to a better understanding of the risk factors and the pathophysiology of NSAID-related hepatotoxicity.

Cheng et al 2004

Cyclooxygenases, the kidney, and hypertension.

Cheng HF, Harris RC.

Hypertension 2004;43(3):525–530.

Selective cyclooxygenase (COX)-2 inhibitors that are in widespread clinical use were developed to avoid side effects of conventional NSAIDs, including gastrointestinal and renal toxicity. However, COX-2 is constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. COX-2 inhibition may transiently decrease urine sodium excretion in some subjects and induce mild to moderate elevation of blood pressure. Furthermore, in conditions of relative intravascular volume depletion and/or renal hypoperfusion, interference with COX-2 activity can have deleterious effects on maintenance of renal blood flow and glomerular filtration rate. In addition to physiological regulation of COX-2 expression in the kidney, increased renal cortical COX-2 expression is seen in experimental models associated with altered renal hemodynamics and progressive renal injury (decreased renal mass, poorly controlled diabetes), and long-term treatment with selective COX-2 inhibitors ameliorates functional and structural renal damage in these conditions.

Blomme et al 2003

Selective cyclooxygenase-2 inhibition does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice.

BACKGROUND: The inducible cyclooxygenase-2 (COX-2) enzyme is upregulated in inflammatory diseases, as well as in epithelial cancers, and has an established role in angiogenesis and tissue repair. OBJECTIVE: Because of these physiological effects and the widespread use of the selective COX-2 inhibitor, celecoxib, we wanted to determine if inhibition of COX-2 would affect incisional skin wound healing. METHODS: Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, we evaluated the role of COX-2 in the wound healing process by comparing the effects of a nonselective COX inhibitor, diclofenac, with a selective COX-2 inhibitor, SC-791. Healing was monitored for up to 28 days postincision histologically and for recovery of wound strength. RESULTS: COX-2 expression was observed over the first week of healing, peaking at day 3 and was not affected by treatment with the selective COX-2 or nonselective COX inhibitors. Infiltrating macrophages, as well as keratinocytes and dermal fibroblasts at the wound site, expressed COX-2. Neither selective COX-2, nor nonselective COX inhibition had a significant effect on the macroscopic or microscopic morphology of the wounds, whereas dexamethasone treatment resulted in epidermal and granulation tissue atrophy. In addition, neither selective COX-2, nor nonselective COX inhibition altered keratinocyte proliferation and differentiation, dermal angiogenesis or the recovery of wound tensile strength, whereas dexamethasone reduced the tensile strength of the wounds by 30-38% throughout the healing period. CONCLUSIONS: These data indicate that selective COX-2 inhibition does not affect the healing of surgical skin wounds.

Analgesic acetaminophen plasma concentrations are not known. We investigated in a randomized, double-blinded study the pharmacokinetics and analgesic efficacy of small- (AS; 20 mg. kg(-1)) and larger- (AL; 40 mg/kg) dose rectal acetaminophen and compared it with the combination (C) of rectal diclofenac (100 mg) and acetaminophen (20 mg/kg) in 65 women undergoing hysterectomy. Suppositories were administered after the induction of a standardized general anesthesia. Pain (measured by using a 10-cm visual analog scale) and morphine consumption (patient-controlled analgesia) were repeatedly assessed for 24 h. Acetaminophen plasma concentrations were measured by using a fluorescence polarization immunoassay. Antipyretic plasma concentrations (10-20 mg/L) after 40 mg/kg acetaminophen were not associated with improved analgesia or decreased opioid requirements; 20 mg/kg acetaminophen produced subtherapeutic plasma levels (<10 mg/L). Maximal plasma concentrations of 17.2 and 10.4 mg/L (P < 0.01, analysis of variance) were achieved after 4.2 and 3.6 h for the AL and AS groups, respectively. The only difference in clinical outcome was lower visual analog scale scores after acetaminophen/diclofenac (C 2.0 versus AS 3.2 and AL 3.4) 4 h after the induction (P < 0.05, analysis of variance). Acetaminophen pharmacokinetics in adults were similar to those observed in children. Analgesic plasma concentrations are likely to be higher than antipyretic plasma levels, which were only attained after twice the recommended rectal dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis. IMPLICATIONS: Acetaminophen pharmacokinetics were comparable in adults and children. Plasma concentrations known to reduce fever did not produce better pain relief and were only achieved after twice the conventional dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis.

Scott et al 1994

The effect of parenteral diclofenac and morphine on duration and height of blockade of continuous epidural infusion of bupivacaine 0.5%.

Scott NB, Forbes DW, Binning AR.

Anaesthesia 1994;49(7):594–596.

Twenty-six patients undergoing abdominal hysterectomy (ASA 1-2) were entered into a double-blind randomised trial to determine: (a) whether diclofenac given intravenously could influence the effective duration of a continuous epidural infusion of bupivacaine 0.5%, and (b) whether morphine given intravenously altered the height of the regressing block. A block to T4 was established pre-operatively and a continuous infusion of 0.5% bupivacaine 8 ml.h-1 ran for 14 h. Thirteen patients received 50 mg diclofenac intramuscularly before surgery repeated at 4 and 10 h later and 13 patients received saline intramuscularly. The height of blockade and pain scores were measured hourly. Effective block duration was defined as regression to T10 or lower and/or a pain score of 2 or more. At this point 10 mg of morphine was given intravenously and the height of the block reassessed. Duration of blockade was not significantly prolonged (p > 0.05), but pain scores were significantly reduced with diclofenac (p < 0.01). Morphine did not alter blockade height. It is concluded that epidural bupivacaine and diclofenac act additively on postoperative pain.

Beck et al 2000a

Rectal paracetamol has a significant morphine-sparing effect after hysterectomy.

Beck DH, Schenk M, Doepfmer U, Kox WJ.

Br J Anaesth 2000a;85(4):658–659.

No abstract available.

Nakayama et al 2001b

PURPOSE: To assess whether perioperative intravenous administration of flurbiprofen, a non-steroidal anti-inflammatory drug, reduced postoperative pain after abdominal hysterectomy. METHODS: Forty-five patients undergoing abdominal hysterectomy were randomly assigned to one of three groups of equal size. A control group (CONT) received a placebo 30 min before and at the end of surgery. The other two groups, PRE and POST, received 1 mg x kg(-1) flurbiprofen iv 30 min before and at the end of surgery, respectively. All patients received identical general and epidural anesthesia. Postoperatively, 50 mg diclofenac pr was given for pain relief on patient demand. One of the authors assessed pain using a 10 cm visual analog scale at rest and during coughing at the first request for diclofenac, and at 15, 24, 48, and 72 hr after surgery. The number of times diclofenac was required during the first 24 hr after surgery was also recorded. RESULTS: The number of diclofenac requests in the PRE (1.8 +/- 0.4) and POST groups (2.0 +/- 0.4) were less than in the CONT group (3.0 +/- 0.4). The PRE group showed lower visual analog scale at rest at 15 and 24 hr and on coughing at 24, 48, and 72 hr after surgery than the CONT and POST groups. CONCLUSION: Intravenous 1 mg x kg(-1) flurbiprofen administered during anesthesia reduces postoperative rescue analgesic requirement after abdominal hysterectomy. Moreover, flurbiprofen is more effective when given before than after surgery.

Gabbott et al 1997

The influence of timing of ketorolac administration on post-operative analgesic requirements following total abdominal hysterectomy.

Gabbott DA, Cohen AM, Mayor AH, Niemiro LA, Thomas TA.

Eur J Anaesthesiol 1997;14(6):610–615.

One hundred and thirty-seven patients were studied to assess whether the timing of a dose of ketorolac affected cumulative morphine requirements during the first 12 post-operative hours. Pain, sedation and nausea scores, respiratory rate and degree of operative blood loss were also recorded. Thirty-six patients (group A) were given placebo injections pre- and intra-operatively. Thirty-one patients (group B) received placebo pre-operatively and ketorolac 30 mg intra-operatively. Thirty-six patients (group C) received ketorolac 10 mg pre-operatively and ketorolac 20 mg intra-operatively and thirty-four patients (group D) were given ketorolac 30 mg pre-operatively and placebo intra-operatively. Post-operative analgesia was with intravenous (i.v.) morphine administered using a patient controlled analgesia (PCA) device. Analysis of variance revealed a significant difference in morphine consumption at 1, 2, 4, 8 and 12 h postoperatively (P < 0.05) between group A (no ketorolac) and groups B, C and D (ketorolac). However, there were no significant differences between groups B, C and D during the study period. Thus, the timing of ketorolac administration made no difference to overall morphine consumption. Pain, nausea, sedation and respiratory rate scores were similar in all four groups. There was a significantly greater blood loss in patients receiving ketorolac (groups B, C and D) compared with those receiving placebo alone (group A).

Bricker et al 1987

Peri-operative blood loss and non-steroidal anti-inflammatory drugs: an investigation using diclofenac in patients undergoing transurethral resection of the prostate

Bricker S, Savage M, Hanning C.

Eur J Anaesthesiol 1987;4(6):429–434.

Peri-operative blood loss was compared in a prospective, randomized double-blind study between two groups of patients undergoing transurethral prostatectomy (TURP) under spinal (subarachnoid) analgesia: the first received the non-steroidal anti-inflammatory drug diclofenac sodium, the second group received placebo. The total blood loss and the blood loss per gram of prostate resected did not differ significantly. Some 80% of patients were completely pain free at 8 and 24 h post-operation, and low pain scores recorded by the remaining 20% of patients supported the conclusion that TURP performed under spinal analgesia is not commonly associated with severe post-operative pain.

Greer et al 1999

Effect of ketorolac and low-molecular-weight heparin individually and in combination on haemostasis.

Greer I, Gibson J, Young A, Johnstone J, Walker I.

Blood Coagul Fibrinolysis 1999;10(6):367–373.

Low-molecular-weight heparins, when used in surgical patients for thromboprophylaxis, may be used concurrently with ketorolac, a non-steroidal anti-inflammatory drug that is used for analgesia. Because these two agents can influence the haemostatic system, it is important to identify any such effect. The haemostatic interaction between dalteparin and ketorolac was assessed in a double-blind, placebo-controlled, randomized, crossover study of healthy male volunteers each given all four combinations of ketorolac/placebo and dalteparin/placebo. The effect of ketorolac and dalteparin on haemostasis was assessed by measuring in-vitro platelet aggregation, anti-factor-Xa, activated partial thromboplastin times and skin bleeding time. The results were analysed for evidence of an interaction between ketorolac and dalteparin. Ketorolac inhibited platelet aggregation in whole blood and platelet-rich plasma. The administration of dalteparin led to a significant increase in levels of anti-factor-Xa and a significant prolongation in the activated partial thromboplastin time, although it remained within the range of the normal population. There was no evidence of any interaction between ketorolac and dalteparin with regard to platelet aggregation, anti-factor-Xa activity or activated partial thromboplastin time. The administration of ketorolac significantly prolonged the skin bleeding time. There was a significant interaction between ketorolac and dalteparin to prolong the bleeding time, although dalteparin alone had no effect on bleeding time. There was an interaction between ketorolac and dalteparin, which affected bleeding times. Such an interaction raises the possibility of haemorrhagic complications developing perioperatively when these agents are used concomitantly. Further studies are required to examine the clinical importance of this interaction.

Niemi et al 1997

Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers.

Niemi T, Taxell C, Rosenberg P.

Acta Anaesthesiol Scand 1997;41(10):1353–1358.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis which may result in impaired platelet function. Because NSAIDs have different abilities to inhibit cyclo-oxygenases we compared the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. METHODS: Ten healthy male volunteers were given ketoprofen 1.4 mg/kg, ketorolac 0.4 mg/kg and diclofenac 1.1 mg/kg in saline i.v. on three different occasions, at more than one-week intervals, in a randomized double-blind crossover study. Platelet function was evaluated before (sample 0), 2 (sample 2) and 24 h (sample 3) after the beginning of the infusion. RESULTS: Two of the volunteers had no secondary platelet aggregation in their aggregation curves before the experiment (sample 0, studied three times) and their results were excluded from the final analysis. Diclofenac inhibited adrenaline (0.9 µg/ml) induced platelet aggregation less (median maximal aggregation 22.5%) than ketoprofen (18.3%) and ketorolac (15.7%) (p < 0.05) in sample 2. In the ketorolac group in sample 3 an impairment of adrenaline (0.9 µg/ml) induced platelet aggregation was still seen (26.7%) (p < 0.05) but not in the other groups. Diclofenac did not affect adenosine diphosphate (ADP) induced platelet aggregation. However, ketorolac caused an impairment in ADP (3 µM and 6 µM ) induced platelet aggregation and ketoprofen in ADP (6 µM ) induced platelet aggregation in sample 2. Bleeding time was prolonged (p < 0.05) after ketoprofen and ketorolac (sample 2) but not after diclofenac. Platelet retention on glass beads was unaffected by the tested drugs. CONCLUSION: Ketoprofen, ketorolac and diclofenac caused a reversible platelet dysfunction. Diclofenac had the mildest effect, while platelet dysfunction was still seen 24 h after the beginning of ketorolac.

Forrest et al 2002

Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery.

BACKGROUND: Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal anti-inflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery. METHODS: This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery. RESULTS: A total of 11,245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0. 17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio=2.65, 95% CI=1.51-4.67) and the comparators (odds ratio=3.58, 95% CI=1.93-6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology). CONCLUSION: We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery.

Stevenson 2004

Aspirin and NSAID sensitivity.

Stevenson DD.

Immunol Allergy Clin North Am 2004;24(3):491–505, vii.

Aspirin and the older nonsteroidal anti-inflammatory drugs (NSAIDs) that block cyclo-oxygenase-1 (COX-1) induce asthma attacks in patients with aspirin-exacerbated respiratory disease and urticaria in patients with chronic idiopathic urticaria. Weak inhibitors of COX-1, such as acetaminophen and salsalate, crossreact also but only with high doses of the drugs. Partial inhibitors of both COX-1 and COX-2, such as nimesulide and meloxicam, also cross-react but only at high drug doses. COX-2 inhibitors do not cross-react; however, all NSAIDs, including the selective COX-2 inhibitors, can sensitize patients and induce urticaria or anaphylaxis on next exposure to the drug.

Cruickshank et al 1996

Pretreatment with controlled-release morphine for pain after hysterectomy.

Cruickshank RH, Spencer A, Ellis FR.

Anaesthesia 1996;51(12):1097–1101.

In a double-blind randomised study, two dosing regimens for controlled-release morphine tablets were compared against placebo to ascertain the extent of prophylactic postoperative pain control in 51 women undergoing abdominal hysterectomy. One group of patients received controlled-release morphine every 12 h for 2 days before surgery, a second group received a single dose of controlled-release morphine 2 h before surgery and a third group received placebo. Patient-controlled analgesia system demands were compared for the first 38 h after surgery and 10-point pain scores and McGill pain questionnaires were compared for the first 6 postoperative days and at 6 weeks after surgery. During the first 2 days after surgery, patients reported high levels of pain which were similar in all groups. Pain scores on the third and fourth postoperative days were significantly lower in those who had a single pre-operative dose of controlled-release morphine compared with placebo and those who had been treated with-morphine every 12 h for 2 days (p = 0.043 and 0.024 for third and fourth day respectively). Patient-controlled analgesia demands were also fewer and less variable in those patients receiving the single dose of morphine 2 h before surgery. The study shows a beneficial analgesic effect of a single pre-operative dose of morphine, but shows no benefit for a more prolonged pre-operative dosing regimen.

Pitschas et al 2000

A double blind placebo-controlled study on the rectal administration of morphine as a premedication in abdominal hysterectomy.

Pitschas D, Jage J, Henrich-Eberl C.

Acute Pain 2000;3(2):70–76.

Benzodiazepines are now commonly used as anxiolytic premedication prior to surgery. However, the role of opioids, as a premedication, has diminished over the last decades and they are no longer routinely used for premedication. Rather, opioids are generally used to treat severe pain in the postoperative period. Studies have shown that both NSAIDs and opioids improve analgesia in the early postoperative period. Until now, there have been no studies investigating the effect of morphine as a rectal premedication in adults in combination with plasma concentrations of morphine. The effect of a rectal premedication with 30 mg of morphine sulphate, on postoperative pain levels and opioid consumption via intravenous patient controlled analgesia (PCA), was investigated in a double blind, placebo-controlled study in 78 patients after abdominal hysterectomy (morphine group n=38; placebo group n=40). The cumulative consumption of opioid within the first four postoperative hours was 26% lower in the morphine group than in the placebo group (p = 0.002). Patients in the morphine group also had less pain. The mean pain scores of all patients premedicated with morphine were significantly lower compared with the placebo group during the entire postoperative period (until the first postoperative morning) (p = 0.013). Neither opioid consumption nor the incidence of opioid-related side effects differed between the two groups. Pharmacokinetic data were determined in seven of these patients: 270 minutes after administration of rectal morphine the mean morphine plasma concentration was above the therapeutic threshold of 10-30 ng ml-1. However, the kinetic data showed considerable interindividual variability; t(max) ranged from 30 minutes in three patients to 90 minutes in four patients after administration of the suppository and C(max) varied from 24.0 to 75.2 ng ml-1 (mean 46.9+/-19.9 ng ml-1). In conclusion, rectal morphine as a premedication in patients prior to abdominal hysterectomy, leads to reduced pain scores and increased efficacy of postoperative PCA within the early postoperative period, without increasing opioid-related side effects.

Fassoulaki et al 1995

Preemptive opioid analgesia does not influence pain after abdominal hysterectomy.

Fassoulaki A, Sarantopoulos C, Zotou M, Papoulia D.

Can J Anaesth 1995;42(2):109–113.

Opioid administration before surgical stimulus may reduce or prevent subsequent pain. We studied the effect of timing of opioid administration on the pain-related behaviour after abdominal hysterectomy. Eighty-five patients scheduled for abdominal hysterectomy were blindly randomized to receive fentanyl 10 micrograms.kg-1 before induction of anaesthesia (FA), after peritoneal incision (FB) or after removal of the uterus (FC), or sufentanil 1 micrograms.kg-1 before induction of anaesthesia (SA) or after peritoneal incision (SB) respectively. All patients received a standard postoperative analgesic regimen. The time from skin closure to the first analgesic request was recorded. Pain was assessed using the VAS and a verbal rating score (VSR 1 = no pain to 6 = intolerable pain) every 30 min until patients asked for the first analgesic, and 24 hr postoperatively. The times from skin closure to the first analgesic request did not differ among the five groups. The VAS scores using the two-way ANOVA with repeated measurements differed among the five groups (F = 4.046, df = 4, 213, P < 0.005). The VAS scores with one-way ANOVA differed among the five groups 30 min postoperatively (F = 4.542, df = 4, 58, P < 0.003), being higher in the FA (6.5 +/- 1.8) and SA (5.9 +/- 2.1) groups than in the FC (3.2 +/- 2.5) group, and at 120 min postoperatively (F = 3.217, df = 4, 18, P < 0.05), being higher in the FA than in the FB group (6.1 +/- 1.5 and 2.6 +/- 1.9 respectively).(Abstract truncated at 250 words)

Kilickan et al 2001

The effect of preemptive intravenous morphine on postoperative analgesia and surgical stress response.

Kilickan L, Toker K.

Panminerva Med 2001;43(3):171–175.

BACKGROUND: Although initial studies of preemptive analgesia showed that preoperative blockade with local anaesthetics or preoperative administration of systemic opioids was more effective in reducing postoperative pain than control conditions involving no treatment, the result of subsequent investigations comparing the effects of preoperative treatment with the same treatment initiated after surgery have produced inconsistent RESULTS. The reasons for the lack of consistency are not clear. Studies about the relationship of preemptive analgesia and both analgesic consumption and surgical stress response are limited. The purpose of this study was to evaluate the effect of preemptive intravenous morphine on both postoperative analgesic consumption and surgical stress response. METHODS: Sixty patients, ASA I or II, aged 20-60, undergoing total abdominal hysterectomy plus bilateral salpingo-oopherectomy and double-blinded were randomly assigned to three groups of 20 patients. Group I (n=20) received 0.15 mg/kg of morphine following induction and placebo saline during peritoneal closure. Group II (n=20) received placebo saline following induction and 0.15 mg/kg of morphine during peritoneal closure. Group III (n=20) received placebo saline both during induction and peritoneal closure. Blood cortisol, glucose levels and leukocyte count were measured in the pre and postoperative period. RESULTS: Postoperative total morphine consumption was significantly lower in group I compared with group III (p<0.001). In all groups, plasma cortisol levels increased significantly within 4 hours of surgery as compared to pre-op values (p<0.001). Plasma glucose also increased to a significantly higher level in all groups in the postoperative 30 min and 8 hours than in the pre-op values (p<0.001). Postoperative leukocytosis was observed in all groups and the leukocyte count was significantly greater during postoperative 24 h than pre-op values (p<0.001). CONCLUSIONS: Preemptive morphine 0.15 mg/kg intravenous has decreased total morphine consumption but has failed to suppress the surgical stress response.

Griffin et al 1997

Few studies using systemic opioids have been adequately designed to demonstrate a preemptive effect. We investigated the preemptive effect of intraoperative large-dose intravenous (I.V.) opioids over a 72-h period after lower abdominal surgery. Thirty-eight ASA physical status I or II patients undergoing abdominal hysterectomy were studied in a prospective, randomized, double-blind design. Group PRE received alfentanil 70 microg/kg over 10 min before surgical incision; Group POST received alfentanil 70 microg/kg over 10 min after incision. Patients received no other intraoperative opioid. Pain was treated in the recovery room with 2-mg I.V. boluses of morphine and was subsequently managed via patient-controlled analgesia (PCA) using morphine sulfate. Visual analog scale pain scores at rest (VAS-R) and on movement (VAS-M) and PCA morphine consumption were recorded for 72 hours. VAS-M and VAS-R scores did not differ at any point, and morphine consumption was similar in both groups over the initial 48 h. Group PRE used significantly less morphine from 48 to 72 h postoperatively (P < 0.02). We conclude that presurgical incisional (i.e., compared with postincisional) large-dose opioid exposure results in a modest, late decrease in postoperative morphine consumption, with no clinical impact on early postoperative pain. Timing of the observed reduction coincides with maximal output of substances implicated in experimental hyperalgesia. Implications: When given before surgical incision, alfentanil, a short-acting narcotic, was associated with a reduction in morphine requirements 48-72 h after surgery. Brief interventions may have a delayed and sustained impact on pain perception, possibly by reducing mechanisms of sensitization.

Dimou et al 2003

Transdermal clonidine: does it affect pain after abdominal hysterectomy?

Dimou P, Paraskeva A, Papilas K, Fassoulaki A.

Acta Anaesthesiol Belg 2003;54(3):227–232.

Clonidine has analgesic properties. We evaluated the analgesic effect of clonidine perioperatively. Forty patients undergoing abdominal hysterectomy received randomly the evening before surgery transdermal clonidine covered with overlay (CLO group) or the overlay alone (CTL group). Ten min before induction they received i.v. clonidine 1 microgram.kg-1 (CLO) or normal saline (CTL). Induction was accomplished with fentanyl 5 micrograms.kg-1, thiopentone 5 mg.kg-1, cis-atracurium 0.15 mg.kg-1 and maintenance with sevoflurane 2% in 70% N2O. Hemodynamic parameters were recorded intraoperatively. Pain was assessed by VAS at rest and movement 2, 4, 6, 8, 24, 48, 72 h and 30 days, postoperatively. During the first 8 h postoperatively all patients received controlled analgesia with fentanyl followed by morphine i.m. 0.15 mg.kg-1 and paracetamol. From 24-72 h postoperatively, patients received 75 mg propoxyphene and 600 mg paracetamol i.m., on demand. Arterial blood pressure was lower in the CLO group 0, 3, 10 min after intubation. There was no difference in pain or fentanyl consumption 8 h postoperatively. The CLO group required less analgesics 24 h postoperatively (p = 0.023). The two groups did not differ in pain or analgesic requirements 72 h and 30 days postoperatively. Clonidine had a weak opioid sparing effect 24 h post-operatively, but did not affect pain in long term.

Caumo et al 2002

In a double blind, placebo-controlled trial, we have assessed the effects of pre-operative anxiolysis on postoperative pain scores in 112 ASA I-II women, aged 18-65 years, scheduled to undergo total abdominal hysterectomy. Subjects were randomly allocated to receive either oral diazepam 10 mg (n=56) or placebo (n=56) pre-operatively. Postoperative anxiety, pain scores, analgesic consumption, and sedation were evaluated at several time points during the first 24 h following surgery. Postoperative pain scores were found to be significantly higher in the diazepam group. Trait and state anxiety showed a significant effect on pain scores, independent of the treatment group. No difference was found between the groups in morphine consumption, but there was a significant reduction in morphine consumption with time.

Burstal et al 2001

PCA ketamine and morphine after abdominal hysterectomy.

Burstal R, Danjoux G, Hayes C, Lantry G.

Anaesth Intensive Care 2001;29(3):246.

Following a standardized general anaesthetic for total abdominal hysterectomy, patients received either patient controlled analgesia (PCA) with morphine 1 mg/ml (group M, n = 33) or morphine 1 mg/ml plus ketamine 2 mg/ml (group K, n = 37) for 48 hours in a randomized, double-blind fashion. In 43 women the area of allodynia around the scar was mapped as a measure of the degree of central sensitization. A significant reduction in the area of allodynia was found in those receiving ketamine with morphine (42 cm2 [interquartile range (IQR) 57] compared with 57 cm2 [IQR 82] z = -2.0, P = 0.04) in those receiving morphine alone. There were no significant differences between the two groups with respect to age, or weight, or between the subgroups within which the area of allodynia was measured with respect to length of incision. No significant differences were found between the groups with respect to pain scores, total or hourly drug consumption, patient satisfaction, nausea scores or antiemetic use. Patients in group K were more likely to require PCA for a shorter period than those in group M (median 40 hours, IQR 26 versus 48 hours IQR 7). Ten patients in group K were withdrawn because of side-effects (dysphoria n = 4, nausea n = 2, pruritus n = 4) compared with one in group M (nausea n = 1) (P = 0.006). The potential usefulness of ketamine after hysterectomy was offset by a high incidence of adverse effects and a lack of opioid-sparing effects, such that combined intravenous ketamine and morphine PCA as used in this study cannot be recommended for routine care.

Goyagi et al 1999

This study was designed to evaluate the effects of oral clonidine premedication on postoperative analgesia by epidural morphine in a prospective, randomized, double-blinded design. Sixty consenting patients, scheduled for total abdominal hysterectomy, were randomly assigned to one of three groups (n = 20 each); the clonidine-morphine group received oral clonidine 5 microg/kg 90 min before arriving in the operating room and epidural morphine 2 mg before induction of general anesthesia, the clonidine-placebo group received oral clonidine 5 microg/kg and no epidural morphine, and the placebo-morphine group received no clonidine and epidural morphine 2 mg. An epidural catheter was placed at the L1-2 or L2-3 interspace, and 1.5% lidocaine was used for surgical anesthesia in all patients. General anesthesia was then induced with propofol, and maintained with a continuous infusion of propofol and 67% nitrous oxide in oxygen during surgery. Four patients were subsequently withdrawn from the study. After surgery, patient-controlled analgesia using IV morphine was used to assess analgesic requirement. Morphine consumptions determined every 6 h after surgery in the clonidine-morphine and placebo-morphine groups were significantly less than the clonidine-placebo group until 12 h after surgery, whereas those of the clonidine-morphine group were significantly less than the placebo-morphine group from 13 to 42 h after surgery. Visual analog (pain) scale (VAS) scores in the clonidine-morphine group were significantly lower than the placebo-morphine group at 48 h at rest, and at 1, 24, 36, and 48 h with movement. Similarly, VAS scores in the clonidine-morphine group were significantly lower than the clonidine-placebo group at 1 and 6 h both at rest and with movement, whereas VAS scores in the clonidine-placebo group were significantly lower than the placebo-morphine group at 24, 36, and 48 h at rest and with movement. The incidence of nausea and pruritus was similar between groups. We conclude that the combination of oral clonidine and epidural morphine produces more potent and longer lasting postoperative analgesia than either drug alone without increasing the incidence of adverse effects after major gynecologic surgeries. IMPLICATIONS: A small dose of epidural morphine is often used for postoperative analgesia. We found that oral clonidine premedication 5 microg/kg improves the analgesic efficacy of epidural morphine without increasing the incidence of adverse side effects.

Beilin et al 2003

Effects of preemptive analgesia on pain and cytokine production in the postoperative period.

BACKGROUND: The postoperative period is associated with increased production of proinflammatory cytokines, which are known to augment pain sensitivity, among other effects. In a previous study, the authors found that patients treated with patient-controlled epidural analgesia (PCEA) exhibited attenuated proinflammatory cytokine response in the postoperative period. In the present study, the authors examined whether preemptive analgesia continued with PCEA may further attenuate the proinflammatory cytokine response and reduce pain sensitivity in the postoperative period. They compared cytokine production in two groups of patients, one receiving PCEA, the other receiving preemptive epidural analgesia continued by PCEA. METHODS: Female patients hospitalized for transabdominal hysterectomy were randomly assigned to one of two pain management techniques: PCEA or preemptive epidural analgesia followed by PCEA (PA + PCEA). Postoperative pain was assessed using the visual analog scale. Blood samples were collected before, 24, 48, and 72 h following surgery. Production of the following cytokines was assessed in stimulated peripheral blood mononuclear cells: interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, IL-1ra, IL-10, and IL-2. RESULTS: Patients of the PA + PCEA group exhibited lower pain scores throughout the 72 h postoperatively, compared with patients of the PCEA group. In patients of the PA + PCEA group in the postoperative period, production of IL-1beta, IL-6, IL-1ra, and IL-10 was significantly less elevated, while IL-2 production was significantly less suppressed. CONCLUSIONS: Proinflammatory cytokines are key mediators of illness symptoms, including hyperalgesia. The present results suggest that preemptive epidural analgesia is associated with reduced postoperative pain and attenuated production of proinflammatory cytokines.

Murga et al 1994

The effect of clonidine on intra-operative requirements of fentanyl during combined epidural/general anaesthesia.

Abdel-Ghaffar et al 1998

PURPOSE: To study the analgesic effect of epidural ketamine on postoperative pain and epidural PCA consumption after total abdominal hysterectomy. METHODS: Sixty-one ASA I–II patients, 34–60 yr were randomly assigned into three groups. Epidural catheters were inserted before induction of anaesthesia. Patients in group I and II received 30 mg ketamine epidurally before induction of anaesthesia or 20 min after skin incision: group III received placebo. Postoperatively, on first analgesia request, sedation score, Visual Analogue Scale (VAS), Prince Henry Score (PHS) and Bromage motor weakness score were taken and followed by an epidural bolus of 9 ml bupivacaine 0.25% + 50 µg fentanyl. Analgesia was maintained by PCA with a mixture of bupivacaine 0.1% + fentanyl 0.001% epidurally. Measurements were repeated at 1, 2, 4, 8, 12 and 24 hr. RESULTS: First analgesia request was 17 +/- 6.8 min in the control group compared with 31.4 +/- 23.8 and 44 +/- 23.1 min for groups I and II respectively. The differences between group III and group I (P < 0.05) and between group III and group II (P < 0.01) were statistically significant. Twenty four hour PCA consumption was 101.2 +/- 47.2, 87 +/- 27 and 162 +/- 38 ml for groups I, II and III respectively. The differences between group III and group I and that between group III and group II were statistically significant (P < 0.001). CONCLUSION: Epidural ketamine 30 mg reduces post hysterectomy pain as evidenced by prolongation of time to first analgesia request and reduction in postoperative epidural PCA consumption. This effect is manifest whether ketamine is given before induction or 20 min after skin incision.

Purpose: The aim of this study was to evaluate preemptive analgesia and its influence on interleukin-6 (IL-6) levels. Methods: Thirty patients scheduled for hysterectomy were randomised in two groups to receive 13 ml bupivacaine 0.25% plus fentanyl (100 [mu]g) before incision and 15 ml of saline after incision (group I, GI), or 15 ml of saline before incision and 13 ml bupivacaine 0.25% plus fentanyl (100 [mu]g) after incision (group II, GII). General anaesthesia was performed using propofol/pancuronium/O2/isoflurane. Postoperative analgesia consisted of epidural bolus doses of 4 ml bupivacaine 0.25% plus fentanyl (50 [mu]g) or dipyrone i.v. on demand. Pain was assessed by visual analogue scale (VAS). IL-6 levels were quantified during the study. Results: Patients in group I had significantly less pain only at arrival in recovery room. The requirements for rescue analgesia were similar in both groups and there were no significant differences in IL-6 concentrations. Conclusions: This study showed no preemptive effect of epidural fentanyl plus bupivacaine on postoperative pain and stress response as measured by IL-6 concentrations.

In a double-blind, randomized study, we investigated 40 patients undergoing abdominal hysterectomy; patients received 0.5% plain bupivacaine 20 ml via a low thoracic extradural catheter and a diclofenac suppository (100 mg), either 30 min before incision (group 1) or 30 min after incision (group 2). All patients received a standard general anaesthetic and no opioid was used before or during operation. Postoperative analgesic requirements were measured using a patient-controlled analgesia (PCA) system. Pain was assessed using a visual analogue scale (VAS) and a verbal pain score (VPS) on movement up to 48 h after operation. There was no significant difference in the time to first request for morphine but consumption of morphine was significantly greater in group 1 at all times except 24 h. There were no significant differences in VAS and VPS pain scores, although both scores were consistently higher in group 1. Patient satisfaction with the quality of analgesia, at 24 h, demonstrated no significant difference between the two groups. The combination of extradural block and diclofenac suppository given before operation did not appear to produce a clinically effective pre-emptive analgesic effect.

Ng et al 2004

Spinal versus epidural anaesthesia for caesarean section.

Ng K, Parsons J, Cyna A, Middleton P.

Cochrane Database Syst Rev 2004;2:CD003765.

BACKGROUND: Regional anaesthesia (spinal or epidural anaesthesia) for caesarean section is the preferred option when balancing risks and benefits to the mother and her fetus. Spinal anaesthesia for caesarean section is thought to be advantageous due to simplicity of technique, rapid administration and onset of anaesthesia, reduced risk of systemic toxicity and increased density of spinal anaesthetic block. OBJECTIVES: To assess the relative efficacy and side-effects of spinal versus epidural anaesthesia in women having caesarean section. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Trials Register (February 2003) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2003). SELECTION CRITERIA: Types of studies considered for review include all published randomised controlled trials involving a comparison of spinal with epidural anaesthesia for caesarean section. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion. Review Manager software was used for calculation of the treatment effect represented by relative risk (RR) and weighted mean difference (WMD) using a random effects model with 95% confidence intervals (CI). MAIN RESULTS: Ten trials (751 women) met our inclusion criteria. No difference was found between spinal and epidural techniques with regards to failure rate (RR 0.98, 95% CI 0.23 to 4.24; four studies), need for additional intraoperative analgesia (RR 0.88, 95% CI 0.59 to 1.32; five studies), need for conversion to general anaesthesia intraoperatively, maternal satisfaction, need for postoperative pain relief and neonatal intervention. Women receiving spinal anaesthesia for caesarean section showed reduced time from start of the anaesthetic to start of the operation (WMD 7.91 minutes less (95% CI -11.59 to -4.23; four studies), but increased need for treatment of hypotension RR 1.23 (95% CI 1.00 to 1.51; six studies). REVIEWERS' CONCLUSIONS: Both spinal and epidural techniques are shown to provide effective anaesthesia for caesarean section. Both techniques are associated with moderate degrees of maternal satisfaction. Spinal anaesthesia has a shorter onset time, but treatment for hypotension is more likely if spinal anaesthesia is used. No conclusions can be drawn about intraoperative side-effects and postoperative complications because they were of low incidence and/or not reported.

Lauretti et al 1998b

STUDY OBJECTIVE: To evaluate the analgesic action of spinal neostigmine as part of a multimodal analgesic therapy approach including spinal neostigmine and spinal fentanyl for postoperative pain relief DESIGN: Randomized, prospective study. SETTING: Teaching hospital. PATIENTS: 50 ASA physical status I and II patients undergoing abdominal hysterectomy. INTERVENTIONS: Patients were assigned to one of five groups (n = 10) to receive 15 mg bupivacaine plus 1 ml of the test drug intrathecally. The control group (CG) received saline as the test drug, the fentanyl group (FG) received 25 microg fentanyl; the neostigmine group (NG) received 25 microg neostigmine; the fentanyl-neostigmine 10 microg group (FNG10) was given 10 microg fentanyl plus 10 microg neostigmine; and the fentanyl-neostigmine 25 microg group (FNG25) received 25 microg fentanyl plus 25 microg neostigmine. Pain and nausea were evaluated using a 10-cm visual analog scale (VAS). MAIN RESULTS: The analgesic consumption, in 24 hours was greatest in CG, next highest in NG, FG, and FNG10 where consumption was the same in the three groups; and least in FNG25 (p < 0.05). The time to first rescue analgesic medication was greatest for FNG25 compared with the other groups (>5 hours compared with 2 to 3 hours; p < 0.05). VAS showed no statistically significant differences for pain impression, intraoperative and postoperative nausea, or occurrence of vomiting (p > 0.05). CONCLUSION: The combination of 25 microg neostigmine with 25 microg fentanyl given intrathecally with 15 mg of hyperbaric bupivacaine delayed postoperative pain and lowered the number of rescue analgesics. Because the better quality of analgesia was obtained with an increased (although not statistically significant difference) incidence of untoward side effects, larger samples should be studied before its routine use is recommended.

Lauretti et al 1998a

A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy.

Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL.

Anesthesiology 1998a;89(4):913–918.

BACKGROUND: Intrathecal neostigmine injection produces analgesia in volunteers and reduces hypotension from intrathecal bupivacaine in animals. Initial clinical trials with neostigmine studied doses of more than 100 microg, but animal studies suggest that smaller doses may be effective. In addition, all controlled clinical trials of neostigmine have come from one Brazilian university. This multicenter, placebo-controlled trial investigated the effects of 25-75 microg intrathecal neostigmine on analgesia and blood pressure in women undergoing vaginal hysterectomy. METHODS: After institutional review board approval was obtained at the three university centers, and after patients gave informed consent, 92 women scheduled for vaginal hysterectomy were randomized to receive an intrathecal injection of 2 ml bupivacaine, 0.75%, in dextrose plus either 1 ml saline or 25, 50, or 75 microg neostigmine. Blood pressure, heart rate, pain and nausea (both assessed by visual analog scale), and intravenous morphine use were recorded during surgery and at specified intervals afterward. RESULTS: Morphine use was reduced similarly by all doses of neostigmine. Only the 75-microg dose of neostigmine increased the nausea score in the recovery room. The incidence of treatment for nausea was greater in patients receiving neostigmine (61%) than in those receiving saline placebo (29%) and was unaffected by neostigmine dose. Neostigmine did not reduce the incidence of hypotension from bupivacaine. CONCLUSION: These data in patients after vaginal hysterectomy suggest that analgesia from intrathecal neostigmine may occur at doses less than 50 microg. In these doses, neostigmine does not reduce spinal bupivacaine-induced hypotension but may increase the need for treatment of nausea.

Yokota et al 2000

PURPOSE: The effects of morphine on natural killer (NK) cell activity were investigated in patients who underwent hysterectomy. METHODS: Forty patients were divided into four groups of ten. The groups received intrathecal 0.5 mg morphine (Group IT0.5), intrathecal 0.1 mg morphine (Group IT0.1) or 10 mg morphine i.v. (Group IV). The remaining ten patients served as controls and received inhalation anesthesia alone (Group C). Blood samples were withdrawn before and two hours after surgery and on postoperative days one and two to determine the blood NK cell activity using a chromium release assay with K562 cells as targets, plasma catecholamines and cortisol levels. The postoperative pain score and side effects were studied in the four groups. RESULTS: In Group IT0.5, the NK cell activity was lower on postoperative day 1 (23.9 +/- 8.4%) than the baseline level (45.7 +/- 13%) before surgery, and recovered on postoperative day 2. In Groups IT0.1, C and IV, the NK cell activities showed no significant changes. In all four groups, neither plasma adrenaline nor noradrenaline concentrations changed. In all four groups, the plasma cortisol levels increased after surgery, on postoperative days 1 and 2. The pain score was lower two hours after surgery and on postoperative day 1 in Group IT0.5 than in the other groups. CONCLUSION: These results suggest that long-lasting analgesic effects of intrathecal 0.5 mg morphine suppress the immune response following abdominal surgery.

Beltrutti et al 2002

Late antinociception and lower untoward effects of concomitant intrathecal morphine and intravenous buprenorphine in humans.

Beltrutti D, Niv D, Ben-Abraham R, Di SS, Weinbroum AA.

J Clin Anesth 2002;14(6):441.

STUDY OBJECTIVE: To evaluate the perioperative antinociceptive effect of intrathecal morphine (a pure mu agonist), intravenous (IV) buprenorphine (a partial mu agonist) or their combination. DESIGN: Randomized, double-blind, placebo-controlled study. SETTINGS: Anesthesiology department of a university-affiliated public hospital. PATIENTS: 45 ASA physical status I, II, and III patients undergoing hysterectomy with general anesthesia. INTERVENTIONS: Preoperative and postoperative regimens consisted of intrathecal morphine 4.3 microg.kg(-1) plus IV 0.9% saline (Group 1), IV buprenorphine 1.3 microg.kg(-1) plus intrathecal saline (Group 2), and intrathecal morphine 4.3 microg.kg(-1) plus IV buprenorphine 1.3 microg.kg(-1) (Group 3; postoperative supplements consisting of IV buprenorphine 1.3 microg.kg(-1) plus intrathecal saline). MEASUREMENTS AND MAIN RESULTS: Group 2 and 3 patients were given three analgesic dosings compared with two dosings in Group 1 (p < 0.001). The duration of action in Group 2 was significantly shorter (p = 0.001) than in the other two groups. The 12-hour postoperative pain intensity and sedation in Group 3 was significantly lower (p < 0.05) than in the other groups. Side effects (mainly pruritus and nausea and vomiting) were significantly fewer (p < 0.05) in Groups 2 and 3 (26% and 28%, respectively) than in Group 1 (46%). CONCLUSIONS: The concomitant administration of intrathecal morphine and IV buprenorphine alleviates pain sensation and minimizes sedation more effectively than when given after the administration of either drug separately. In addition, IV buprenorphine affords a reduction in side effects.

Rane et al 2000

BACKGROUND: Adenosine (Ado) is known, from studies in both animals and humans, to produce antinociception when administered systemically or intrathecally (IT). The current aim was to evaluate, in a placebo-controlled, randomised, double-blind study, whether IT adenosine given before surgery could reduce anaesthetic requirement and the need of opioids during 48 h after visceral surgery. METHOD: Forty women (37-66 years, ASA I and II) scheduled for elective hysterectomy were included. Before inducing the standardised O2/N2O/isoflurane/fentanyl anaesthesia, the patients received an IT injection of either adenosine (500 microg in 1 ml volume) or placebo 1 ml (saline). Intraoperative anaesthetic drug doses and haemodynamics were recorded. Postoperative pain was assessed by visual analogue scale. For postoperative analgesia, cetobemidone was provided via intravenous patient-controlled analgesia (PCA). RESULTS: During surgery, there were no differences between groups in anaesthetic requirement or haemodynamic parameters. Postoperative cetobemidone requirements were similar in both groups (median 48 mg for adenosine/50 mg for saline) during the first 48 postoperative hours. CONCLUSION: IT adenosine did not influence the requirement of anaesthetic drug or postoperative analgesics after hysterectomy.

Dakin et al 1996

BACKGROUND AND OBJECTIVES. This study was undertaken to determine whether preoperative spinal anesthesia with local anesthetics would exert a pre-emptive effect on postoperative analgesia by reducing neural afferent stimulation. METHODS. The authors studied 38 healthy women undergoing total abdominal hysterectomy. Patients were randomly allocated to two groups: group A received a spinal block (T3-S5) prior to induction of anesthesia and surgery, while in group B the block was performed after surgery prior to extubation of the trachea. Patient-controlled analgesia morphine was administered to both groups during the first 24 postoperative hours. RESULTS. Pain and sedation scores at 6, 12, and 24 hours were similar in the two groups. Cumulative morphine consumption at 6 and 24 hours after surgery was similar in both groups; however at 12 hours more morphine was needed in group A (P < .02). CONCLUSIONS. The authors were unable to demonstrate that spinal block with bupivacaine before surgery, as opposed to after surgery, decreased the requirement of morphine in the postoperative period.

HYPOTHESIS: Subcutaneous infiltration of bupivacaine before skin incision can reduce postoperative pain and modulate the stress response. METHODS: In a randomized study on pain relief after hysterectomy 29 patients were referred into one of three groups, receiving 30 ml of bupivacaine 0.25% with adrenaline, 30 ml of saline or no infiltration along the line of the proposed incision 10 min before start of surgery. A Visual Analogue Scale was used for repeated pain ratings. Postoperative pain relief was provided with patient-controlled analgesia with intravenous morphine 0.04 mg/kg. Lockout time was 10 min. The immunological and endocrine stress response to trauma was reflected by blood interleukin-6 (IL-6) and cortisol concentrations measured during 72 h following skin incision. RESULTS: There were large individual variations in the accumulated postoperative consumption of morphine at 20 h after start of surgery. It was significantly reduced in patients receiving infiltration of bupivacaine. They used 39 mg (9-62) median (range) of intravenous morphine whereas the patients in the saline group used 65 mg (47-120) and patients in the control group used 54 mg (36-130) (P < 0.05). Significant elevation of plasma IL-6 and serum cortisol levels appeared in all groups with peak values at 3 h. There were no differences between the groups. There was a correlation between cortisol and IL-6. Six of the 29 patients had a postoperative infection which was reflected in increased IL-6 levels. CONCLUSION: Preoperative subcutaneous infiltration of bupivacaine significantly reduced the postoperative consumption of intravenous morphine.

Hannibal et al 1996

Preoperative wound infiltration with bupivacaine reduces early and late opioid requirement after hysterectomy.

Hannibal K, Galatius H, Hansen A, Obel E, Ejlersen E.

Anesth Analg 1996;83(2):376–381.

We conducted a randomized, double-blind trial to evaluate the early and late analgesic effect of preoperative wound infiltration with bupivacaine 0.25% (40 mL) compared to placebo (NaCl 0.9%, 40 mL) in patients undergoing major surgery. Forty-one patients scheduled for elective hysterectomy during general anesthesia were included. The pain management focused on pain prevention, including preoperative administration of nonsteroidal antiinflammatory drugs (NSAIDs), and peroperative administration of opioids. Postoperatively patients received buprenorphine and/or acetaminophen on demand. A significant difference between treatments was evident in the 3-day postoperative trial period. With identical pain scores in the two groups, the requested total amount of buprenorphine was greater in the placebo group (2.0 [0-5.1] mg) (median and [range]) than in the bupivacaine group (0.8 [0-2.8] mg) (P < 0.05). The demand for analgesics occurred earlier in those who received placebo (225 min) than in those who received bupivacaine (345 min), but did not reach the level of significance. In conclusion, preoperative wound infiltration with bupivacaine improved immediate and late postoperative pain management after hysterectomy compared to placebo.

Sarac et al 1996

The effect and timing of local anesthesia in laparoscopic cholecystectomy.

Sarac AM, Aktan AO, Baykan N, Yegen C, Yalin R.

Surg Laparosc Endosc 1996;6(5):362–066.

Although postoperative pain following laparoscopic cholecystectomy (LC) is less intense than that after open surgery, postoperative morbidity nonetheless increases with LC. The aim of this study was to investigate whether local anesthetic infiltration of trocar sites during LC decreased postoperative pain and, if so, to find the optimum timing for local anesthesia (LA). Seventy patients undergoing LC were randomized into three groups. In the first (control group, n = 25) 3 ml of 0.9% NaCl was subcutaneously infiltrated around each 5-mm trocar site, 4 ml around each 10-mm site. In the second group (n = 20), the same volume of local anesthetic was administered in the same manner prior to surgery, and in the third group (n = 25) an identical dose of local anesthetic was infiltrated at the end of surgery. A visual analog scale was given to all patients, who were asked to record their pain intensity at 1, 3, 5, 7, and 12 h postoperatively. Pethidine HCl 1 mg/kg i.m. was given to those whose pain intensities were greater than 5. The mean pain intensities were 7.6, 5.9, and 5.1 in the control, preoperative, and postoperative LA groups, respectively. In the preoperative LA group, 50% of patients and in the postoperative LA group 28% of patients required analgesics compared with 76% in the control group. The main pain intensities and analgesic requirements were significantly lower in the postoperative LA group compared with other groups. We conclude that local anesthesia during LC reduces postoperative pain and that infiltration of trocar sites following surgery offers better pain relief than local anesthetic given just before the incision.

Homoeopathic potencies of arnica have been used for many years to aid postoperative recovery. The effects of arnica C30 on pain and postoperative recovery after total abdominal hysterectomy were evaluated in a double-blind, randomized, controlled study. Of 93 women entered into the study, 20 did not complete protocol treatment: nine were excluded because they failed to comply with the protocol, nine had their operations cancelled or changed within 24 h and two had to be withdrawn because of the recurrence of previously chronic painful conditions. Those who did not complete protocol treatment were equally divided between the arnica (nine patients) and placebo groups (11 patients). 73 patients completed the study, of whom 35 received placebo and 38 received arnica C30. The placebo group had a greater median age and the arnica group had slightly longer operations; nevertheless, no significant difference between the two groups could be demonstrated. We conclude that arnica in homoeopathic potency had no effect on postoperative recovery in the context of our study.

Cheung et al 2003

A controlled trial of psycho-educational interventions in preparing Chinese women for elective hysterectomy.

Cheung LH, Callaghan P, Chang AM.

Int J Nurs Stud 2003;40(2):207–216.

The objective of this study was to investigate the effect of a cognitive intervention (distraction and reappraisal) with information given pre-operatively on post-operative outcomes of Chinese women having an abdominal hysterectomy. Using a controlled trial, 48 Chinese women having elective hysterectomy received the cognitive intervention with information (experimental group). A control group (n=48) received information alone. Outcome measures used in the study were post-operative anxiety and pain, requests for analgesia and patient satisfaction. The results show that women in the experimental group reported lower post-operative anxiety scores, lower pain scores and higher levels of satisfaction than women in the control group. There were no statistically significant differences in post-operative requests for analgesia between the groups. It is concluded that a cognitive intervention such as distraction and reappraisal may have significant clinical benefits and improve the care of women having an elective hysterectomy.

Ridgeway et al 1982

Psychological preparation for surgery: a comparison of methods.

Ridgeway V, Mathews A.

Br J Clin Psychol 1982;21 (Pt 4):271–280.

Sixty hysterectomy patients were randomly assigned to one of three types of psychological preparation prior to surgery, while an additional 10 patients declined psychological help. Twenty patients received information about the surgical procedure and its effects, another 20 were instructed in a cognitive coping technique, and the remainder were given general information about the ward. Interventions were shown to have different effects on a number of pre- and post-surgical measures; notably on knowledge about hysterectomy, analgesic usage, reported days of pain after discharge, and belief in the usefulness of intervention methods. Whereas information about surgery enhanced knowledge and usefulness ratings, cognitive coping appeared to have most effect on indices of recovery. Patients declining preparation responded badly immediately after surgery, but made a satisfactory recovery after discharge. Cognitive coping methods seem to be an effective way of managing specific worries about the operation, and it is suggested that this underlies differences in patterns of recovery following surgery.

Mogan et al 1985

Effects of preoperative teaching on postoperative pain: a replication and expansion.

Mogan J, Wells N, Robertson E.

Int J Nurs Stud 1985;22(3):267–280.

This study was designed to test the effectiveness of brief relaxation training on postoperative pain, replicating and extending a study of Flaherty and Fitzpatrick (1978). A two-group pre- and post-test experimental design was used to determine if vital signs, analgesic consumption, anxiety, self-reported incisional pain sensation and distress differ in postsurgical patients who have or have not received relaxation training. Seventy-two adult, elective abdominal surgery patients were randomly assigned to treatment groups. Subjects in both groups were visited on the eve of surgery. Experimental subjects were taught a relaxation technique. Equal time was spent with control subjects. Following surgery all subjects were observed during ambulation. Vital signs were measured pre- and postoperatively, as were self-report of pain sensation and distress. Results showed that distress caused by painful sensations was significantly lower for experimental subjects (F (1, 53) = 4.69, p = 0.03). Vital signs, analgesic consumption and self-reported pain sensation were not altered by relaxation training. These findings only partially agree with those of Flaherty and Fitzpatrick. Additional analyses by type of surgery (cholecystectomy and hysterectomy) showed hysterectomy subjects reported less pain sensation and distress and used less analgesics than cholecystectomy subjects.

Jorgensen et al 2001

Effect of peri- and postoperative epidural anaesthesia on pain and gastrointestinal function after abdominal hysterectomy.

This study tested the hypothesis that high dose systemic alfentanil administered before and during abdominal hysterectomy would pre-empt post-operative pain to a greater extent than administration of either low dose alfentanil or no alfentanil perioperatively. Patients (ASA 1 or 2) were randomly assigned to group 1 (n = 15), no opioid; group 2 (n = 15), low dose alfentanil; or group 3 (n = 15), high dose alfentanil. Anaesthesia was induced in group 1 with midazolam and thiopentone and was maintained with isoflurane and 70% N2O in O2. Anaesthesia was induced in group 2 with midazolam, thiopentone and i.v. alfentanil (30 microg kg(-1)), and was maintained with isoflurane, 70% N2O in O2, and bolus doses of i.v. alfentanil (10-20 microg kg(-1)) every hour. Anaesthesia was induced in group 3 with midazolam and i.v. alfentanil (100 microg kg(-1)), and was maintained with 70% N2O in O2, and an infusion of i.v. alfentanil (1-2 microg kg(-1) min(-1)). Blood samples were drawn at 30 and 120 min after surgery and assayed for plasma alfentanil. Morphine consumption and VAS pain scores were consistently lowest in group 3 over the 48 h study period. A composite measure of pain and morphine consumption was significantly lower in group 3 than group 2 up to 6 h after surgery, and significantly lower than group 1 up to 12 h. No adverse effects were observed. A 6-month follow-up did not reveal any significant differences among the three groups. It is concluded that intra-operative high dose alfentanil anaesthetic pre-empts post-operative pain after abdominal hysterectomy, but the effects are small and of short duration. Surgical procedures carried out under general anaesthesia using standard (and even high) doses of opioids intraoperatively provide suboptimal protection from the injury barrage brought about by incision and subsequent noxious surgical events.

Segerdahl et al 1997

BACKGROUND: Adenosine (ADO), and stable analogs thereof, have been shown to exert antinociceptive action in cutaneous and deep somatic pain under experimental and clinical conditions in animals and in humans. The aims of this randomized double-blind placebo-controlled study were to evaluate if a low dose of intravenous (i.v.) ADO could reduce the requirements of volatile anesthetic and postoperative opioid in connection to hysterectomy, where visceral nociception significantly contributes to pain. METHODS: Forty-three women, age 32-65 years, ASA I and II, scheduled for abdominal hysterectomy, were assigned to receive an i.v. infusion of either adenosine, 80 micrograms.kg-1.min-1, or placebo during surgery. Anesthesia was maintained with isoflurane (ISO)/N2O/ O2 inhalation. Postoperatively, a reduced dose of 40 micrograms.kg-1.min-1 was continued for 3 h. RESULTS: The end-tidal (ET-) ISO was equal between groups before surgery. During surgery, the ISO requirement was increased, compared to the preoperative level, in the placebo group, while the requirement declined in the ADO group. The overall ISO requirement in the ADO group was reduced by 36% (P < 0.002). The first 24 h postoperative opioid requirement, with equal resting pain in both groups, was 18% (P < 0.05) lower in the ADO group. CONCLUSION: A low dose of perioperative adenosine infusion in abdominal hysterectomy reduces the requirements of volatile anesthetic and postoperative opioid analgesic.

Gilliland et al 1996

An investigation of the potential morphine sparing effect of midazolam.

Gilliland HE, Prasad BK, Mirakhur RK, Fee JP.

Anaesthesia 1996;51(9):808–811.

The effect of a bolus and continuous infusion of midazolam on postoperative morphine consumption was assessed in a placebo-controlled, double-blind, randomly allocated trial of 50 patients undergoing elective abdominal hysterectomy. Patients in the trial group received a bolus dose of midazolam 5 mg.70 kg-1 at induction followed by an infusion at a rate of 1 mg.70 kg-1.h-1 over the next 48 h. Morphine consumption in the midazolam group was significantly lower in the first 12 h postoperatively (p < 0.02) but there was no significant difference between the two groups thereafter. Patients in the midazolam treated group had lower pain scores over the first 24 h. Also, a significantly greater number of patients in the midazolam group required no antiemetic medication over the 48 h study period (p < 0.05). Assessment of sedation revealed no significant difference between groups. We conclude that low dose midazolam has a significant, but short-lived, morphine sparing effect.

Franklin et al 1990

Tryptophan-morphine interactions and postoperative pain.

Franklin KBJ, Abbott FV, English MJM, Jeans ME, Tasker RAR, Young SN.

Pharmacology, Biochemistry & Behavior 1990;35(1):157–163.

Patients undergoing abdominal surgery were infused with saline or the 5-hydroxytryptamine (5-HT) precursor tryptophan starting in the operating room and continuing for three hours in the recovery room. There was a nonsignificant trend for patients who received tryptophan to have higher pain scores. In the saline-treated patients, plasma tryptophan was below the range for normal healthy subjects, and there was a strong positive relationship between plasma tryptophan and morphine requirements. These data, taken together with animal data obtained using the formalin pain test, suggest that a 5-HT system in the brain can antagonize the dissociative state produced by morphine, which helps patients to tolerate pain. When plasma tryptophan falls below normal levels, brain 5-HT falls and morphine requirements are reduced. While tryptophan may potentiate spinal 5-HT function to decrease nociceptive afference in some circumstances, there may be clinical conditions in which the use of tryptophan is contraindicated.

Wilder-Smith et al 1998

Sensory changes and pain after abdominal hysterectomy: a comparison of anesthetic supplementation with fentanyl versus magnesium or ketamine.

Wilder-Smith OH, Arendt-Nielsen L, Gaumann D, Tassonyi E, Rifat KR.

Anesth Analg 1998;86(1):95–101.

Drugs interacting with opioid or N-methyl-D-aspartate (NMDA) receptors may have differing effects on post-surgical sensory changes, such as central inhibition or spinal excitation. We compared the effect of supplementing isoflurane/N2O/O2 anesthesia with an opioid agonist (fentanyl [n = 15]) or two drugs inhibiting the NMDA system differently (magnesium, ketamine [n = 15 in each group]) on sensory changes after abdominal hysterectomy. Electric sensation, pain detection, and pain tolerance thresholds were determined (preoperatively and 1, 4, 24 h, and 5 days postoperatively) in arm, thoracic, incision, and leg dermatomes together with pain scores and cumulative morphine consumption. Thresholds relative to the arm were derived to unmask segmental sensory changes hidden by generalized changes. Absolute thresholds were increased 1-24 h, returning to baseline on Day 5, without overall differences among drugs. Fentanyl thresholds were lower 1 h and higher 5 days postoperatively compared with magnesium and ketamine; thresholds were lower at 24 h for magnesium versus ketamine. Relative thresholds increased compared with baseline only with fentanyl (1-4 h); none decreased. Pain scores and morphine consumption were similar. Thus, all adjuvants suppressed spinal sensitization after surgery. Fentanyl showed the most, and magnesium the least, central sensory inhibition up to 5 days postoperatively, with different patterns of inhibition directly postsurgery versus later. Differences in sensory processing were not reflected in clinical measures. Implications: We studied the effects on postsurgical sensory processing of general anesthesia supplemented by drugs affecting opioid or N-methyl-D-aspartate receptors using sensory thresholds. Generalized central sensory inhibition, differently affected by the drugs, predominated after surgery. All drugs suppressed spinal excitation. Clinical pain measures did not reflect sensory change.

Aida et al 1999

The effectiveness of preemptive analgesia varies according to the type of surgery: a randomized, double-blind study.

Aida S, Baba H, Yamakura T, Taga K, Fukuda S, Shimoji K.

Anesth Analg 1999;89(3):711–716.

The reliability of preemptive analgesia is controversial. Its effectiveness may vary among anatomical areas or surgical types. We evaluated preemptive analgesia by epidural morphine in six surgery types in a randomized, double-blind manner. Pain intensity was rated using a visual analog scale, a verbal report, and a measurement of postsurgical morphine consumption. Preemptive analgesia was effective in limb surgery and mastectomy, but ineffective for gastrectomy, hysterectomy, herniorrhaphy, and appendectomy. Relief of postsurgical pain in hemiorrhaphy was more rapid than that in the other surgery types. Preemptive analgesia was effective in limb surgery and mastectomy, but not in surgeries involving laparotomy, regardless of whether the surgery was major (gastrectomy and hysterectomy) or minor (herniorrhaphy and appendectomy). These results suggest that viscero-peritoneal nociception is involved in postsurgical pain. The abdominal viscera and peritoneum are innervated both heterosegmentally (in duplicate or triplicate by the vagus and/or phrenic nerves) and segmentally (by the spinal nerves). Therefore, supraspinal and/or cervical spinal neurons might be sensitized, despite the blockade of the segmental nerves with epidural morphine. The rapid retreat of the pain after hemiorrhaphy suggests that central sensitization remits soon after minor surgery, but that in appendicitis, it may be protracted by additional noxious stimuli, such as infection. IMPLICATIONS: Epidural preemptive analgesia was reliably effective in limb and breast surgeries but ineffective in abdominal surgery, suggesting involvement of

Jorgensen et al 1982

Influence of epidural morphine on postoperative pain, endocrine-metabolic, and renal responses to surgery. A controlled study.

Jorgensen BC, Andersen HB, Engquist A.

Acta Anaesthesiol Scand 1982;26(1):63–68.

In order to assess the analgesic properties of epidural low-dose morphine and its possible influence on the adrenocortical, hyperglycemic, renal, electrolyte and leukocyte responses to surgery and nitrogen excretion, a double-blind randomized study was undertaken in 14 otherwise healthy patients admitted for hysterectomy under halothane, N2O/o2 anesthesia. Before induction of anesthesia, an epidural catheter was introduced into the lumbar epidural space. After induction of anesthesia, either morphine 4 mg in 10 ml saline or 10 ml saline was injected into the epidural space, according to the allocation. Postoperatively, the degree of pain was evaluated by mean of a visual analogue scale (0-10). When pain score exceeded 5 points during the 24 -h trial, either 4 mg morphine in saline or saline was given epidurally. If the pain score did not decrease more than 2 points after an epidural injection, morphine was given parenterally (5 mg i.v. +5 mg i.m.). The results showed that pain scores, duration of pain relief and doses of morphine differed significantly between groups (P less than 0.05). Plasma concentration of cortisol and glucose, plasma-and urine electrolytes, 24-h creatinine and free-water clearances, diuresis, fluid balance, leukocyte count and nitrogen excretion differed insignificantly between groups. In conclusion, epidural low-dose morphine is a superior alternative to conventional postoperative pain treatment because of greater and longer lasting pain relief, without apparent side-effects. The measured endocrine-metabolic and renal response did not differ between groups, indicating that low-dose epidural morphine does not inhibit afferent neurogenic stimuli from the site of surgical trauma.

In a randomized, double-blind, placebo-controlled trial, the value of adding clonidine to a low-dose epidural regimen for postoperative pain treatment was assessed. Twenty-four patients scheduled for hysterectomy during combined thoracic epidural (bupivacaine and morphine) and general anesthesia were studied. Postoperative analgesia consisted of epidural bupivacaine (5 mg/h) and morphine (0.1 mg/h) for 12 h. In addition, the patients randomly received clonidine (75 micrograms), followed by an infusion of 18.75 micrograms/h or saline solution (placebo) epidurally. Pain was evaluated at rest, during cough, and during mobilization every hour. Sensory level of analgesia was evaluated by pinprick. We found no significant difference in pain scores at rest between the clonidine and placebo groups but an enhanced analgesic effect by clonidine during cough and mobilization (P less than 0.05). Arterial blood pressure decreased significantly during clonidine infusion and remained lower than in the control group throughout the study. We conclude that a continuous low-dose epidural clonidine infusion enhances analgesia from a combined low-dose epidural bupivacaine and morphine regimen after hysterectomy; however, the concomitant decrease in arterial blood pressure during epidural clonidine deserves further study before such a regimen can be recommended.

Richards et al 1998

Epidural anaesthesia as a method of pre-emptive analgesia for abdominal hysterectomy.

Richards JT, Read JR, Chambers WA.

Anaesthesia 1998;53(3):296–298.

The effect of pre- versus postincisional epidural blockade without the use of systemic opioids was investigated in a randomised, double-blind study of two groups of 25 patients undergoing abdominal hysterectomy performed under general anaesthesia. The first group received, via a lumbar epidural catheter, 0.9% saline (16 ml) 15 min prior to surgical incision and 0.5% bupivacaine (15 ml) and fentanyl 50 micrograms (1 ml) 15 min prior to skin closure. The second group of 25 patients received the same amount of bupivacaine and fentanyl 15 min pre-incision and saline prior to skin closure. Visual analogue pain scores and patient-controlled morphine consumption were measured at specified times for 48 h. We were unable to detect any significant difference in either of the outcome measures of the two groups and thus were unable to demonstrate that epidural blockade using local anaesthetic and opioid has a pre-emptive effect.

Nakayama et al 2001a

STUDY OBJECTIVE: To evaluate the effects of epidurally administered neostigmine on pain after abdominal hysterectomy. DESIGN: Prospective, randomized, double-blind study. SETTING: Teaching hospital. PATIENTS: 45 ASA physical status I adult patients scheduled for abdominal hysterectomy. INTERVENTIONS: All patients received identical general and epidural anesthesia. At the end of the surgery, they received epidural bupivacaine (10 mg) with either saline (control group, n = 15), 5 micro g/kg (5-micro g group, n = 15), or 10 micro g/kg neostigmine (10-micro g group, n = 15). Postoperatively, 50 mg diclofenac suppository was given for pain relief on patient demand. MEASUREMENTS AND MAIN RESULTS: The time to first diclofenac administration and the number of times diclofenac was required during the first 24 postoperative hours were recorded. Pain was assessed using a 10-cm visual analog pain scale (VAS) at rest at the first diclofenac request, and at 15 and 24 hours after surgery. The time to first diclofenac administration was significantly longer (p < 0.05) in the 10-micro g group (223 +/- 15 min) than in the control (78 +/- 17 min) or 5-micro g groups (88 +/- 18 min). However, epidural neostigmine at both doses did not reduce the number of postoperative diclofenac administrations. There were no differences in VAS among the three groups. CONCLUSIONS: Epidural neostigmine of 10 micro g/kg in bupivacaine provides a longer duration of analgesia than does bupivacaine alone or with 5 micro g/kg of neostigmine after abdominal hysterectomy.

Cobby et al 1997

Wound infiltration with local anaesthetic after abdominal hysterectomy.

Cobby TF, Reid MF.

Br J Anaesth 1997;78(4):431–432.

The study was performed to investigate if wound infiltration with 20 ml of 0.5% bupivacaine after abdominal hysterectomy improved analgesia and reduced morphine requirements from a patient-controlled analgesia system during the first 6 h after operation. Forty patients undergoing abdominal hysterectomy were allocated randomly to one of two groups. The study was performed in a double-blind controlled manner. Morphine requirements in the first 6 h after operation were similar in both the control (30.3 mg) and bupivacaine (29.0 mg) groups. Cumulative hourly morphine requirements did not differ significantly between the two groups. Pain scores assessed by visual analogue were similar in both groups.

Richman et al 1994

Local infiltration of ketorolac and bupivacaine for postoperative pain control in hysterectomy patients.

Klein et al 2000

Infiltration of the abdominal wall with local anaesthetic after total abdominal hysterectomy has no opioid-sparing effect.

Klein JR, Heaton JP, Thompson JP, Cotton BR, Davidson AC, Smith G.

Br J Anaesth 2000;84(2):248–249.

We have measured the effect of infiltration of the deep and superficial layers of the abdominal wound on morphine consumption and pain for 48 h after operation, in 40 patients undergoing total abdominal hysterectomy, in a double-blind randomized study. Patients received wound infiltration with 0.9% normal saline 40 ml or 40 ml of 0.25% bupivacaine with epinephrine 1:200,000. There were no significant differences between groups in morphine consumption, linear analogue scores for pain at rest or on movement, nausea or sedation during the first 48 h after operation. We conclude that infiltration of the deep and superficial layers of the wound of a Pfannenstiel incision with local anaesthetic solution did not confer additional analgesia in patients undergoing major gynaecological surgery.

Pain is the dominant complaint after laparoscopic cholecystectomy. No study has examined the combined effects of a somato-visceral blockade during laparoscopic cholecystectomy. Therefore, we investigated the effects of a somato-visceral local anesthetic blockade on pain and nausea in patients undergoing elective laparoscopic cholecystectomy. In addition, all patients received multi-modal prophylactic analgesic treatment. Fifty-eight patients were randomized to receive a total of 286 mg (66 mL) ropivacaine or 66 mL saline via periportal and intraperitoneal infiltration. During the first 3 postoperative h, the use of morphine and antiemetics was registered, and pain and nausea were rated hourly. Daily pain intensity, pain localization, and supplemental analgesic consumption were registered the first postoperative week. Ropivacaine reduced overall pain the first two hours and incisional pain for the first three postoperative hours (p < 0.01) but had no apparent effects on intraabdominal or shoulder pain. During the first 3 postoperative h, morphine requirements were lower (p < 0.05), and nausea was reduced in the ropivacaine group (p < 0.05). Throughout the first postoperative week, incisional pain dominated over other pain localizations in both groups (p < 0.01). We conclude that the somato-visceral local anesthetic blockade reduced overall pain during the first 2 postoperative h, and nausea, morphine requirements, and incisional pain were reduced during the first 3 postoperative h in patients receiving prophylactic multi-modal analgesic treatment. IMPLICATIONS: A combination of incisional and intraabdominal local anesthetic treatment reduced incisional pain but had no effect on deep intraabdominal pain or shoulder pain in patients receiving multimodal prophylactic analgesia after laparoscopic cholecystectomy. Incisional pain dominated during the first postoperative week. Incisional infiltration of local anesthetics is recommended in patients undergoing laparoscopic cholecystectomy.

Gallagher et al 2001

Prospective validation of clinically important changes in pain severity measured on a visual analog scale.

Gallagher EJ, Liebman M, Bijur PE.

Ann Emerg Med 2001;38(6):633–638.

Ali et al 1998

Intraperitoneal bupivacaine or lidocaine does not provide analgesia after total abdominal hysterectomy.

Ali PB, Cotton BR, Williamson KM, Smith G.

Br J Anaesth 1998;80(2):245–247.

We have compared pain scores at rest and on standardized movement, and morphine consumption using patient-controlled analgesia in 60 patients who had undergone total abdominal hysterectomy. Patients were allocated randomly to one of three groups: in the saline group, 0.9% sodium chloride 50 ml was administered into the pelvic cavity before closure of the peritoneum; in the second group, the solution administered was 20 ml of 0.5% bupivacaine solution with epinephrine 1:200,000 diluted with saline to a final volume of 50 ml; in the third group, the solution used was 20 ml [corrected] of 2% lidocaine with epinephrine 1:200,000 diluted with saline to a final volume of 50 ml. We found that there was no significant difference between the three groups in visual analogue pain scores at 8, 12, 36 or 48 h after operation at rest or on movement, and no significant difference in sedation or dose of antiemetic administered. Mean morphine consumption in the first 24 h was 54.6 (SEM 5.9) mg in the saline group, 55.5 (6.4) mg in the bupivacaine group and 52.5 (5.3) mg in the lidocaine group. In the second 24 h, morphine consumption was 34.9 (6.6) mg, 28.1 (3.5) mg and 28.0 (3.5) mg in the three groups, respectively. We conclude that i.p. administration of local anaesthetic solution into the pelvic cavity did not confer appreciable analgesia in patients undergoing abdominal hysterectomy.

Williamson et al 1997

Intraperitoneal lignocaine for pain relief after total abdominal hysterectomy.

Williamson KM, Cotton BR, Smith G.

Br J Anaesth 1997;78(6):675–677.

In this preliminary randomized study, we have measured pain scores at rest and on movement, 24 and 48 h after operation in 19 control patients, who received 50 ml of saline i.p., and in 20 test patients, in whom 50 ml of saline solution containing lignocaine 200 mg and adrenaline 1:500,000 were instilled into the peritoneal cavity after total abdominal hysterectomy. We found that there was no difference in linear analogue scores for nausea, pain on movement or morphine consumption after operation between the two groups, but pain scores at rest were significantly lower in the lignocaine group at 24 and 48 h compared with the saline group. In the lignocaine group, blood sampling over a 3-h period revealed a mean maximum serum concentration of 0.4 microgram ml-1 at 3 h and a highest concentration in any patient of 0.87 microgram ml-1.

Narchi 1995

[New routes for infiltration: intraperitoneal injections].

Narchi P.

Cah Anesthesiol 1995;43(3):267–272.

Intraperitoneal administration of local anaesthetics is frequently used during gynaecological laparoscopy and especially after laparoscopic sterilization where the solution may be instilled, sprayed or infiltrated around the clip or the rings. In addition, the subdiaphragmatic instillation of local anaesthetics by the surgeon during laparoscopy is followed by a decrease in the intensity of postoperative scapular pain which is known to last 2-3 days and is due to some degree of residual pneumoperitoneum. After laparoscopic cholecystectomy, the analgesic effects of the administration of local anaesthetics via the intraperitoneal route remain controversial. The pharmacokinetic data available which confirm the safety of doses up to 100 mg of bupivacaine or 800 mg of lidocaine, should encourage the use of larger doses, especially after cholecystectomy.

Møiniche et al 2000

Local anesthetic infiltration for postoperative pain relief after laparoscopy: A qualitative and quantitative systematic review of intraperitoneal, port-site infiltration and mesosalpinx block.

Møiniche S, Jorgensen H, Wetterslev J, Dahl JB

Anesth Analg 2000; 90: 899–912.

In a systematic review, we evaluated randomized controlled trials (RCTs) of peripheral local anesthetics (LA) compared with placebo or no treatment in the control of postoperative pain after laparoscopic surgery. A total of 41 trials with data from 2794 patients were considered appropriate for analysis. Of these 41 RCTs, 13 evaluated intraperitoneal LA after cholecystectomy, four RCTs assessed intraperitoneal LA after other procedures, eight RCTs evaluated port-site infiltration after various procedures, 12 RCTs evaluated mesosalpinx or fallopian tube block after sterilization, and four RCTs considered combined LA regimens. Outcome measures were pain scores, analgesic consumption, and time to first analgesic request. Efficacy was estimated by significant difference (P < 0.05), as reported in the original reports, and by calculation of the weighted mean difference of visual analog scale pain scores between treatment groups. Improved pain relief was observed in seven of the 13 RCTs of intraperitoneal LA after cholecystectomy and in four RCTs of other procedures. A statistically significant weighted mean difference of -13 mm visual analog scale (95% confidence intervals [CI]: -20 to -6) in favor of the treatment groups was observed after cholecystectomy. Three of eight trials of port-site infiltration showed significant differences but questionable clinical importance and validity in two; weighted mean difference was not statistically significant between treatment groups (95% CI -9 to 1). All RCTs of mesosalpinx or fallopian tube block after sterilization showed improved pain relief with a statistically significant weighted mean difference of -19 mm (95% CI -25 to -14) in favor of treatment groups. Data of combined regimens were positive, however, sparse. We conclude that there was evidence for a statistically significant but clinically questionable, important effect of intraperitoneal LA for postoperative pain control. There was evidence for a significant but short-lasting effect of mesosalpinx/fallopian tube block after sterilization, but there was a lack of evidence for any important effect of port-site infiltration. Data from combined regimens were too sparse for conclusions. IMPLICATIONS: A systematic review summarizes, through transparent methodology, available information from randomized, controlled trials to produce the best available evidence-based estimate of a "true" clinical effect of an intervention. This systematic review confirms intraperitoneal and mesosalpinx local anesthetic block, not port-site infiltration, to have some impact on postoperative pain after laparoscopy.

Ellstrom et al 1998

Pain and pulmonary function following laparoscopic and abdominal hysterectomy: a randomized study.

Ellstrom M, Olsen MF, Olsson JH, Nordberg G, Bengtsson A, Hahlin M.

Acta Obstet Gynecol Scand 1998;77(9):923–928.

BACKGROUND: The aim of this study was to evaluate pain and pulmonary function the first two days after abdominal and laparoscopic hysterectomy. METHODS: Women scheduled for abdominal hysterectomy were prospectively randomized to either laparoscopic (n=20) or abdominal (n=20) hysterectomy. Analgesics were self-administered by the patients by means of a programable infusion pump containing morphine. Postoperative pain was evaluated using a visual analog scale. Oxygen saturation was measured with an oxymeter. Pulmonary function was assessed using a peak flow meter measuring peak expiratory flow and a vitalograph measuring forced vital capacity and forced expiratory volume in one second. RESULTS: Pain scores were lower after laparoscopic hysterectomy at the first (p<0.05) and second postoperative day (p<0.01). Lung function was impaired on days 1 and 2 postoperatively, measured as peak expiratory flow, forced vital capacity and forced expiratory volume in one second, in both groups compared to the preoperative values. The patients undergoing laparoscopic hysterectomy had less impairment of lung function measured by peak expiratory flow (p<0.01), forced vital capacity (p<0.05) and forced expiratory volume in one second (p<0.05) the first postoperative day compared to the patients undergoing abdominal hysterectomy. The second postoperative day differences between the groups remained for peak expiratory flow (p<0.05) and forced expiratory volume in one second (p<0.05). CONCLUSIONS: Laparoscopic hysterectomy results in less pain and less impairment of respiratory function compared to abdominal hysterectomy.

Howard et al 1993

A comparison of laparoscopically assisted vaginal hysterectomy and abdominal hysterectomy.

Howard FM, Sanchez R.

J Gynecol Surg 1993;9(2):83.

The goal of this study was to compare laparoscopically assisted vaginal hysterectomy (LAVH) with total abdominal hysterectomy (TAH). We performed a prospective comparison of the hospital courses of 30 women, 15 undergoing LAVH and 15 undergoing TAH, in a teaching hospital setting. Analysis of variance (ANOVA) was used, with statistical evaluation of differences by Student's t-test for normally distributed data and Kruskal-Wallis for data with dissimilar variances. Fourteen of fifteen patients scheduled for LAVH had their surgery completed without need of a laparotomy. In the LAVH group, (1) mean surgical time was 50 minutes longer, (2) blood loss, complications, and hospital costs were not statistically different, (3) hospital days averaged 1 1/2 less, and (4) postoperative pain ratings and medication requirements were significantly decreased, compared with the TAH group. In many cases, LAVH may be reasonably performed instead of an indicated TAH.

Garry et al 2004

The eVALuate study: two parallel randomised trials, one comparing laparoscopic with abdominal hysterectomy, the other comparing laparoscopic with vaginal hysterectomy.

OBJECTIVE: To compare the effects of laparoscopic hysterectomy and abdominal hysterectomy in the abdominal trial, and laparoscopic hysterectomy and vaginal hysterectomy in the vaginal trial. DESIGN: Two parallel, multicentre, randomised trials. SETTING: 28 UK centres and two South African centres. PARTICIPANTS: 1380 women were recruited; 1346 had surgery; 937 were followed up at one year. Primary outcome Rate of major complications. RESULTS: In the abdominal trial laparoscopic hysterectomy was associated with a higher rate of major complications than abdominal hysterectomy (11.1% v 6.2%, P = 0.02; difference 4.9%, 95% confidence interval 0.9% to 9.1%) and the number needed to treat to harm was 20. Laparoscopic hysterectomy also took longer to perform (84 minutes v 50 minutes) but was less painful (visual analogue scale 3.51 v 3.88, P = 0.01) and resulted in a shorter stay in hospital after the operation (3 days v 4 days). Six weeks after the operation, laparoscopic hysterectomy was associated with less pain and better quality of life than abdominal hysterectomy (SF-12, body image scale, and sexual activity questionnaires). In the vaginal trial we found no evidence of a difference in major complication rates between laparoscopic hysterectomy and vaginal hysterectomy (9.8% v 9.5%, P = 0.92; difference 0.3%, -5.2% to 5.8%), and the number needed to treat to harm was 333. We found no evidence of other differences between laparoscopic hysterectomy and vaginal hysterectomy except that laparoscopic hysterectomy took longer to perform (72 minutes v 39 minutes) and was associated with a higher rate of detecting unexpected pathology (16.4% v 4.8%, P = < 0.01). However, this trial was underpowered. CONCLUSIONS: Laparoscopic hysterectomy was associated with a significantly higher rate of major complications than abdominal hysterectomy. It also took longer to perform but was associated with less pain, quicker recovery, and better short term quality of life. The trial comparing vaginal hysterectomy with laparoscopic hysterectomy was underpowered and is inconclusive on the rate of major complications; however, vaginal hysterectomy took less time.

Richardson et al 1995

Is laparoscopic hysterectomy a waste of time?

Richardson RE, Bournas N, Magos AL.

Lancet 1995;345(8941):36–41.

Laparoscopic hysterectomy (LH) is a way to avoid laparotomy. However, there is evidence that most women treated by abdominal hysterectomy are suitable for vaginal surgery. To test this hypothesis, and to determine the relative merits of laparoscopic and vaginal hysterectomy (VH) and the best technique for LH, we prospectively studied 98 women who had relative contraindications for vaginal surgery by traditional criteria. 75 underwent LH and 23 VH. The LH group included 22 women who had been assigned to this route of surgery as part of a prospective randomised controlled comparison with VH (23 women). Surgery was completed with the intended technique in 93.9% of cases. 5 women in the LH group (6.7%) and 2 in the VH group required laparotomy or additional procedures. In the prospective randomised study LH took longer than VH (mean duration 131 vs 77 min). VH was the faster procedure, irrespective of uterine size and need for oophorectomy. With LH, the operative time increased as more of the hysterectomy was carried out with laparoscopic rather than vaginal dissection. Complication rates, blood loss, analgesia requirements, and recovery were similar for the two techniques. Our study confirms that most hysterectomies could be performed vaginally, and that LH is a much slower procedure. If LH is done, it should be converted to a vaginal procedure as early as possible to reduce the overall operating time. LH does seem to be a waste of time for most patients.

Behtash et al 2001

To peritonealise or not to peritonealise? A randomised trial at abdominal hysterectomy in Iran.

We conducted a trial to determine whether non-closure of the visceral and parietal peritoneum alters the intraoperative or post-operative course at abdominal hysterectomy. This was a parallel-group double-blind randomised controlled trial was performed on 66 women who underwent abdominal hysterectomy with or without salpingo-oophorectomy. Twenty-seven were allocated to the control 'closed' group and 39 women to the study 'open' group. The main outcome measures were operative time, estimated blood loss, postoperative pain assessed by visual analogue scale and amount of postoperative analgesia. The study was conducted in the Department of Gynecological Oncology in a university teaching hospital. The operative time was shorter (P<0.05) and the time to ambulation without assistance was significantly shorter in study group. There were no difference in postoperative pain, blood loss, amount of postoperative analgesia and antibiotics in the two groups. Peritoneal closure at abdominal hysterectomy provides no immediate postoperative benefits while unnecessarily lengthening surgical time and anaesthesia exposure. We suggest that the traditional practice of visceral and parietal closure be abolished at abdominal hysterectomy.

Persson et al 2001

Perioperative hypothermia and postoperative opioid requirements.

Persson K, Lundberg J.

Eur J Anaesthesiol 2001;18(10):679–686.

BACKGROUND AND OBJECTIVE: Hypothermia may alter the disposition of opioids. Because opioids are commonly used as analgesics in the postoperative period, it is of clinical interest to clarify whether perioperatively developed hypothermia affects postoperative opioid requirements. METHODS: Fifty-nine patients undergoing subtotal hysterectomy were prospectively randomized and either treated intraoperatively with forced air warming, or served as controls covered with conventional blankets without active warming. Both groups received postoperative patient-controlled analgesia with the opioid ketobemidone. Total analgesic requirements, demands, analgesic requirements over 6-h intervals and pain scores were measured for 48 h. Core temperature at the tympanic membrane and ambient room temperature were measured during the perioperative period. RESULTS: There were no postoperative differences in analgesic requirements or pain intensity between normothermic and hypothermic patients. Patients treated with warm air had an up to 1 degree C higher core temperature from 0.5 h after anaesthesia induction until almost 2 h postoperatively. The actively warmed patients also had a lower intraoperative blood loss than the hypothermic patients (186 +/- 27 mL vs. 308 +/- 47 mL; P < 0.05). CONCLUSION: In a clinical setting, opioid requirements do not seem to be affected by mild postoperative hypothermia after lower abdominal surgery.

Briggs 1996

Surgical wound pain: a trial of two treatments.

Briggs M.

J Wound Care 1996;5(10):456.

In order to compare postoperative incisional pain intensity, a prospective randomised controlled trial was conducted with two patient groups: a treatment group (treated with a film dressing left intact until suture removal) and a control group (treated with the existing wound-care protocol of a dry dressing removed after 48 hours). Patient-controlled analgesia consumption and infection rates in the two groups were also compared. A sample of 30 patients undergoing total abdominal hysterectomy was selected. Incisional wound pain, measured using a visual analogue scale (at rest, on movement and a 24-hour average) and the McGill Pain Questionnaire were recorded daily until discharge (four days). The pain scores were not significantly different between the groups on Days 1 or 2 postoperatively. However, on Day 3 (when the wounds in the dry dressing group were exposed), there was a statistically significant difference in 24-hour average pain. Those whose wounds were covered with the film dressing experienced less pain and requested fewer non-steroidal anti-inflammatory drugs on Day 3. Maintaining a cover over a surgical wound until suture removal appears to promote pain relief when compared to exposing wounds to the air. A film dressing was useful in this respect as it allowed inspection of the wound without removing the dressing.

Horowitz et al 2003

OBJECTIVE: To determine if the type of operative incision influences the adequacy of surgical staging in patients with uterine cancer. METHODS: All patients with uterine cancer referred to the Swedish Medical Center Cancer Institute for adjuvant radiotherapy between June 1, 1989, and June 1, 1999, who underwent comprehensive surgical staging and for whom complete records could be obtained were eligible. Data on type of incision, weight, medical comorbidities, histology, total number and distribution of lymph nodes (LN), estimated blood loss, complications, and length of stay were abstracted retrospectively. Statistical analysis with two-tailed Student t test, chi(2), Fisher's exact, and Kaplan-Meier survival curves were performed. RESULTS: Five hundred four women with uterine cancers were referred to the Cancer Institute with 332 meeting inclusion criteria. A vertical midline incision (ML) was used in 236 (72%) while 96 (28%) received a Pfannenstiel incision (PI). No panniculectomies were performed. There were no statistically significant differences in age, weight, stage, histology, comorbidities, or estimated blood loss between the ML and PI groups. ML was associated with significantly more intraoperative and postoperative complications (34 vs. 7; P = 0.003). When compared to ML a greater number of total LN (21.0 vs. 16.8; P = 0.001) and a comparable number of pelvic LN (13.7 vs. 12.2; P = 0.14) were procured through a PI. More patients with a ML (72% vs. 63%; P = 0.13) had para-aortic lymph nodes (PALN) dissected; however, when obtained equivalent numbers of nodes were removed (3.52 vs. 4.36; P = 0.14). Overall, the median length of stay was statistically shorter for those patients operated on via a PI (4 vs. 3 days; P = 0.007). The projected 5-year disease-free (83% vs. 85%) and disease-specific (87% vs. 85%) survival was unaffected by incision. In the heaviest quartile of patients (>180 lb), a statistically greater number of total LN (23.3 vs. 16.5; P = 0.005) and pelvic LN (16.7 vs. 11.5; P = 0.05) were obtained with a PI. Again, PALN were sampled more frequently (67% vs. 56%; P = 0.45) in patients with a ML, but the mean LN yield was no different (3.91 vs. 5.20; P = 0.37). Likewise, in this heaviest quartile, there were no statically significant differences in operative complications (7 vs. 1; P = 0.43) with either incision. CONCLUSIONS: Comprehensive surgical staging for uterine cancers can be adequately performed through a PI without greater morbidity or mortality. By using this surgical approach, patients with uterine cancer can benefit from the inherent benefits previously described for PI. Appropriate patient selection, however, is necessary.

Kearns et al 2001

BACKGROUND: Electrocautery is used increasingly for tissue dissection, although fears of excessive scarring and poor wound healing have curtailed its widespread use for skin incision. This study compared electrosurgical incision with traditional scalpel incision. METHODS: One hundred patients requiring elective midline laparotomy were randomized prospectively to either scalpel or diathermy incision. Parameters measured included incision time, wound size, wound blood loss, total intraoperative blood loss and postoperative wound pain. All wound complications were recorded. RESULTS: The two groups did not differ significantly in relation to patient or wound characteristics. Laparotomy incisions using diathermy were significantly quicker than scalpel incisions (mean(s. e.m.) 6.1(0.4) versus 7.5(0.5) s/cm2; P < 0.04). There was significantly less blood loss in the diathermy group compared with the scalpel group (0.8(0.1) versus 1.7(0.3) ml/cm2; P = 0.002). Postoperative pain scores were significantly lower in the diathermy group for the first 48 h after operation (P < 0.05). Morphine requirements were also significantly lower over the first 5 postoperative days in the diathermy incision group (P < 0.04). There was no difference between groups in wound complications before discharge and at the 1-month follow-up. CONCLUSION: Electrosurgical midline incision in elective surgery has significant advantages over scalpel use on the basis of incision time, blood loss, early postoperative pain and analgesia requirements.

Block et al 1991

Efficacy of therapeutic suggestions for improved postoperative recovery presented during general anesthesia.

Block RI, Ghoneim MM, Sum PST, Ali MA.

Anesthesiology 1991;75(5):746.

There have been claims that the postoperative course of patients may be improved by presentation during general anesthesia of therapeutic suggestions which predict a rapid and comfortable postoperative recovery. This study evaluated the effectiveness of such therapeutic suggestions under double-blind and randomized conditions. A tape recording predicting a smooth recovery during a short postoperative stay without pain, nausea, or vomiting was played during anesthesia to about half the patients (N = 109), while the remaining, control patients were played a blank tape instead (N = 100). The patients were primarily undergoing operations on the fallopian tubes, total abdominal hysterectomy, vertical banding gastroplasty, cholecystectomy, and ovarian cystectomy or myomectomy. The anesthesia methods consisted of either isoflurane with 70% nitrous oxide in oxygen to produce end-tidal concentrations of 1.0, 1.3, or 1.5 MAC; or 70% nitrous oxide in oxygen combined with high or low doses of opioids. Assessments of the efficacy of the therapeutic suggestions in the recovery room and throughout the postoperative hospital stay included: the frequency of administration of analgesic and antiemetic drugs; opioid doses; the incidence of fever; nausea, retching, and vomiting; other gastrointestinal and urinary symptoms; ratings of pain; ratings of anxiety; global ratings of the patients' physical and psychological recoveries by the patients and their nurses; and length of postoperative hospital stay. There were no meaningful, significant differences in postoperative recovery of patients receiving therapeutic suggestions and controls. These negative results were not likely to be due to insensitivity of the assessments of recovery, as they showed meaningful interrelations among themselves and numerous differences in recovery following different types of surgery. Widespread utilization of therapeutic suggestions as a routine operating room procedure seems premature in the absence of adequate replication of previously published positive studies.

Nilsson et al 2001

Improved recovery after music and therapeutic suggestions during general anaesthesia: a double-blind randomised controlled trial.

Nilsson U, Rawal N, Unestahl LE, Zetterberg C, Unosson M.

Acta Anaesthesiol Scand 2001;45(7):812–817.

PURPOSE: This study was designed to determine whether music or music in combination with therapeutic suggestions in the intra-operative period under general anaesthesia could improve the recovery of hysterectomy patients. METHODS: In a double-blind randomised clinical investigation, 90 patients who underwent hysterectomy under general anaesthesia were intra-operatively exposed to music, music in combination with therapeutic suggestion or operation room sounds. The anaesthesia was standardised. Postoperative analgesia was provided by a patient-controlled analgesia (PCA). The pain scores were recorded by means of a visual analogue scale. Nausea, emesis, bowel function, fatigue, well-being and duration of hospital stay were studied as outcome variables. RESULTS: On the day of surgery, patients exposed to music in combination with therapeutic suggestions required less rescue analgesic compared with the controls. Patients in the music group experienced more effective analgesia the first day after surgery and could be mobilised earlier after the operation. At discharge from the hospital patients in the music and music combined with therapeutic suggestion group were less fatigued compared to the controls. No differences were noted in nausea, emesis, bowel function, well-being or length of hospital stay between the groups. CONCLUSION: This double-blind study has demonstrated that intra-operative music and music in combination with therapeutic suggestions may have some beneficial effects on postoperative recovery after hysterectomy. Further controlled studies are necessary to confirm our results.

McLintock et al 1990

OBJECTIVE--To establish whether positive suggestions given to a patient under general anaesthesia reduce postoperative pain and analgesic requirements. DESIGN--Prospective double blind randomised study. SETTING--Operating theatre and gynaecology ward of a teaching hospital. PATIENTS--63 Woman undergoing elective abdominal hysterectomy were randomised to be played either a tape of positive suggestions or a blank tape during the operation through a personal stereo system. INTERVENTIONS--Three women were withdrawn from the study. Anaesthesia was standardised for all of the women. Postoperative analgesia was provided through a patient controlled analgesia system for the first 24 hours. Pain scores were recorded every six hours. MAIN OUTCOME MEASURES--Morphine consumption over the first 24 hours after the operation; pain scores. RESULTS--Mean morphine requirements were 51.0 mg (95% confidence interval 42.1 to 60.0 mg in the women played positive suggestions; and 65.7 mg (55.6 to 75.7 mg) in those played a blank tape. The point estimate (95% confidence interval) for the difference of means was 14.6 mg (22.4%) (1.9 (2.9%) to 27.3 mg (41.6%] (p = 0.028). Pain scores were similar in the two groups. CONCLUSION--Positive intraoperative suggestions seem to have a significant effect in reducing patients' morphine requirements in the early postoperative period.

Christensen et al 1993

We have studied the effects of electroacupuncture at classical acupuncture points, applied before and during surgery in patients undergoing hysterectomy, on postoperative pain and metabolic stress responses in a prospective, randomized and patient-blinded manner. Fifty otherwise healthy women were allocated randomly to receive or not receive electroacupuncture. Electroacupuncture was begun 20 min before skin incision and continued to the end of surgery. All patients received similar general anaesthesia and all received patient-controlled analgesia (PCA) after operation. Postoperative pain in the two groups was evaluated by recording analgesic requirements by PCA and by pain-rating performed by patients and nursing staff. There were no significant differences between the two groups in postoperative analgesic requirements, pain-rating or metabolic stress responses.

Tang et al 2002

Effect of parecoxib, a novel intravenous cyclooxygenase type-2 inhibitor, on the postoperative opioid requirement and quality of pain control.

Blackburn et al 1995

STUDY OBJECTIVE: To investigate the efficacy, opioid-sparing effects and any reduction in adverse events of a continuous intravenous (i.v.) infusion of ketorolac following lower abdominal surgery. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Inpatient elective gynecologic surgical patients. PATIENTS: 60 ASA physical status I or II patients aged 18 to 70 years scheduled for elective abdominal hysterectomy. INTERVENTIONS: Following standardized preparation and anesthesia, continuous i.v. infusions of either ketorolac or placebo were administered for 24 hours postoperatively with a patients' standardized postoperative protocol. Supplementary analgesia was administered by an i.v. patient-controlled analgesia (PCA) system. MEASUREMENTS AND MAIN RESULTS: A significantly lower proportion of the patients in the ketorolac group (6%) rated their pain at 24 hours as moderate or severe compared with patients in the placebo group (34%) (p = 0.04). Mean 24-hour morphine consumption was significantly lower in the ketorolac group (43 mg; SEM 5 mg) compared with the placebo group (55 mg SEM 5 mg) (p = 0.02). There was no significant difference in the incidence of postoperative hypoxemia between the groups with respect to mean times per hour spent with oxygen saturation (SPO2) less than 85%, more than 85% but less than 90%, or more than 90% but less than 94%, mean hourly SPO2, or the incidence and duration of severe hypoxemic episodes. Nausea and vomiting were the only significant adverse events, and they occurred in 30% of patients in both groups. CONCLUSION: Intravenous infusion of ketorolac combined with morphine delivered via a PCA device would appear to be a valuable method of providing balanced analgesia following lower abdominal surgery.

Ng et al 2002a

Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient?

Ng A, Parker J, Toogood L, Cotton BR, Smith G.

Br J Anaesth 2002;88(5):714–716.

BACKGROUND: The aim of this prospective, double-blind, randomized, placebo-controlled clinical trial was to investigate the opioid-sparing effects of rectal diclofenac following total abdominal hysterectomy. METHODS: Forty ASA I-II patients, aged 20-60 yr, were randomized to receive identical-looking suppositories of either diclofenac 75 mg or placebo, twice daily. All patients were given a standardized anaesthetic, with intravenous morphine via a patient-controlled analgesia device and either diclofenac or placebo for postoperative analgesia. RESULTS: The median 24 h morphine consumption (interquartile range) was significantly higher (P=0.02) in the placebo group [59 (45-85) mg] than in the diclofenac group [31 (14-65) mg]. In comparison with the placebo group, there were significant reductions in total pain score in the diclofenac group at rest (P=0.04) and on movement (P<0.01). Total (SD) sedation score was significantly lower (P=0.04) in the diclofenac group [90 (73) mm] than in the placebo group [148 (89) mm]. Total (interquartile range) nausea score was significantly lower (P<0.01) in the diclofenac group [14 (0-53) mm] than in the placebo group [64 (30-109) mm]. There was no significant difference between the two groups of patients in episodes of vomiting or number of rescue antiemetics. CONCLUSIONS: Rectal diclofenac reduces morphine consumption, improves postoperative analgesia, and reduces the incidence of adverse effects such as sedation and nausea.

Cobby et al 1999

Rectal paracetamol has a significant morphine-sparing effect after hysterectomy.

Kim et al 2001

Plasma levels of interleukin-6 and interleukin-10 are affected by ketorolac as an adjunct to patient-controlled morphine after abdominal hysterectomy.

Kim MH, Hahm TS.

Clin J Pain 2001;17(1):72–77

OBJECTIVE: Because morphine affects various immune functions, patient-controlled analgesia with morphine may further deteriorate the immune mechanisms after surgery. Therefore, the purpose of this study was to determine differences between morphine patient-controlled analgesia and a combination of morphine and ketorolac in interleukin-6 and interleukin-10 responses, and in analgesia and morphine-related side effects. DESIGN: Prospective study. PATIENTS: Twenty-two patients who underwent abdominal hysterectomy were classified randomly into two groups: (1) patient-controlled analgesia with morphine; and (2) patient-controlled analgesia with a combination of morphine and ketorolac. Blood samples to measure cytokines were collected at preoperatively, immediately postoperatively, and 2 hours, 4 hours, and 24 hours postoperatively. OUTCOME MEASURES: Plasma was separated and frozen until the analysis of cytokines using enzyme-linked immunosorbent assays. Postoperative pain was assessed using a visual analog score. Sedation was checked based on a protocol developed at the Samsung Medical Center. RESULTS: In the two groups, interleukin-6 increased immediately postoperatively, and it remained consistent for 24 hours. Interleukin-10 concentrations peaked at 2 hours postoperatively and progressively decreased. Cytokine concentrations between the two groups were significantly different for interleukin-6 24 hours postoperatively (p = 0.026) and for interleukin-10 4 hours postoperatively (p = 0.045). Total analgesic use was not different, but morphine consumption was significantly different (p = 0.037 at 4 hours postoperatively, p = 0.015 at 24 hours postoperatively). Pain scores, sedation, and side effects were unaffected by the patient-controlled analgesia regimen. CONCLUSIONS: The authors conclude that supplementation using ketorolac plus administration of morphine modifies cytokine responses and may contribute to immune augmentations during postoperative periods.

Black et al 1990

Intramuscular ketorolac and morphine during patient-controlled analgesia (PCA) after hysterectomy: does PCA lock-out time reveal an efficacy limitation of ketorolac?

Black AMS, Goodman NW, Bullingham RES, Lloyd J.

Eur J Anaesthesiol 1990;7(1):9–17.

Analgesic requirements were studied in women who used patient-controlled analgesia (PCA) to give themselves either ketorolac (n = 14) or morphine (n = 15) intramuscularly for up to 22 h after abdominal hysterectomy performed under standardized general anaesthesia. The first 18 patients used a Bard PCA device, which had a lock-out time of 3 min, and the last six in each group used an Oxford Prodac, which had no lock-out time. Supplementary morphine was prescribed to cover pain that patients considered uncontrollable by PCA. Unexpectedly, the ketorolac patients using the Prodac took larger doses of ketorolac than did those using the Bard. The consumptions of morphine did not change with the PCA device. This is consistent with ketorolac having an efficacy limitation that was revealed because the Prodac had no lock-out time. Comparing the consumption of supplementary morphine by the ketorolac patients with the total morphine consumption in the morphine patients suggested that ketorolac had a morphine-sparing effect of about 80%. Fewer of the ketorolac users were nauseated.

We compared the analgesic efficacy and safety of tramadol, a new pure agonistic central analgesic, with that of three nonsteroidal anti- inflammatory drugs (NSAIDs) in the control of postoperative pain. A total of 160 patients undergoing abdominal hysterectomy participated in this randomized, double-blind study. Four treatment groups were established: tramadol, metamizole, ketorolac, and lysine clonixinate, with 40 patients in each group. Analgesics were administered using continuous infusion plus patient-controlled analgesia. During this 24-hour study, pain was assessed by using a visual analog scale. The number of boluses required per patient, the number of patients requiring supplementary analgesia, the presence of nausea or vomiting, the need for antiemetics, and an evaluation of overall efficacy also were recorded during the first 24 hours after surgery. The analgesic efficacy of tramadol was found to be greater than that of the three NSAIDs. Tramadol also was statistically significantly better than the other three agents with regard to the number of boluses required per patient (1.6 versus 4.4 for metamizole, 4.5 for ketorolac, and 5.3 for lysine clonixinate) and the number of patients requiring supplementary analgesia (1 patient versus 5 for metamizole, 11 for ketorolac, and 11 for lysine clonixinate). Nausea and vomiting were common in all four groups, especially in patients treated with metamizole, but the need for antiemetics was significantly lower with tramadol and lysine clonixinate. With regard to overall efficacy, as rated by the physician, excellent and very good results were obtained in 79.5% of the patients in the tramadol group, compared with 57.5%, 57.5%, and 50% of those in the metamizole, ketorolac, and lysine clonixinate groups, respectively (P < 0.05 or better). The results of this study confirm that tramadol, a central analgesic, is better for controlling postoperative pain than the NSAIDs with which it was compared. <100> *COPYRIGHT ELSEVIER SCIENCE B.V. - ALL RIGHTS RESERVED*

Ilias et al 1996

Pain control after hysterectomy: an observer-blind, randomised trial of lornoxicam versus tramadol.

Ilias W, Jansen M.

Br J Clin Pract 1996;50(4):197–202.

This 24-hour, randomised, double-blind, placebo-controlled study compared the efficacy and tolerability of intravenous injections of lornoxicam 4 mg and 8 mg with tramadol 50 mg in 78 female patients aged 20-65 years with moderate to intolerable postoperative pain following mainly hysterectomy. Patients who received lornoxicam 8 mg had a significantly (p < 0.05) longer time to first remedication than placebo recipients and tended to have a greater reduction in pain intensity and a longer time to withdrawal due to "non-response' than tramadol and placebo patients. Lornoxicam was well tolerated at both doses and was associated with a lower incidence of adverse events than tramadol. Thus, intravenous lornoxicam at a dose of 8 mg is superior to placebo and at least as effective as intravenous tramadol 50 mg in relieving moderate to intolerable post-hysterectomy pain. Furthermore, lornoxicam seems to possess a more favourable tolerability profile than tramadol.

Torres et al 2001

Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study.

BACKGROUND AND OBJECTIVES: We assessed the efficacy and safety of dipyrone in comparison with tramadol in the relief of early postoperative pain following abdominal hysterectomy. METHODS: A total of 151 women between 18 and 60 years of age undergoing abdominal hysterectomy during general anesthesia participated in a randomized, double-blind, controlled, multicenter study. Seventy-three patients received dipyrone and 78 received tramadol. Patients received an intravenous loading dose of the study drug immediately after operation followed by intravenous (IV) maintenance infusion and IV on-demand boluses up to a maximum number of predetermined doses/day of 8 g dipyrone and 500 mg tramadol. The duration of the study was 24 hours. RESULTS: The mean (SD) number of boluses in the dipyrone group was 3.8 (2.4) and 3.5 (2.5) in the tramadol group (95% confidence interval, -0.455 to 1.175), and the percentage of patients requiring rescue IV morphine (dipyrone 26.9%, tramadol 26.8%) was not statistically significant. Other analgesic efficacy parameters, such as pain intensity differences, sum of pain intensity differences, pain relief assessed by the patient, or patients who required the maximum number of demand doses, were not different between treatment groups. A significantly higher percentage of adverse gastrointestinal effects was found in patients given tramadol (42.1%) than in patients given dipyrone (20.2%) (P

In a randomized, double-blind, placebo-controlled trial, we assessed the value of adding rectal piroxicam to a low-dose epidural regimen for postoperative pain relief. Forty-four patients scheduled for major upper abdominal surgery during combined thoracic epidural (bupivacaine + morphine) and general anesthesia were studied. Postoperative analgesia was achieved by using epidural bupivacaine (10 mg/h) plus morphine (0.2 mg/h) for 72 h. In addition, the patients randomly received a placebo or rectal piroxicam (40 mg 12 h before surgery, 20 mg with premedication, and 20 mg every 24 h for 72 h). Pain was evaluated every 4 h at rest, during coughing on demand, and during mobilization. The sensory level of analgesia was evaluated by pinprick. We found no significant difference between piroxicam and placebo with regard to postoperative pain scores or need for supplementary analgesics. Thus, we were unable to demonstrate enhanced analgesia by adding piroxicam to an otherwise very effective low-dose epidural bupivacaine and morphine treatment after upper abdominal surgery.

Collis et al 1995

Is there any clinical advantage of increasing the pre-emptive dose of morphine or combining pre-incisional with postoperative morphine administration?

Collis R, Brandner B, Bromley LM, Woolf CJ.

Br J Anaesth 1995;74(4):396–399.

Pre-emptive treatment with an i.v. infusion of morphine 10 mg at induction reduces postoperative analgesic requirement and wound hypersensitivity compared with the same dose administered at the end of operation. Increasing the dose of preemptive morphine may potentially reduce postoperative pain further, while administering morphine at the end of operation, in addition to the beginning, may reduce pain generated by the sensory activity elicited from the wound in the immediate postoperative period. To examine this we have conducted a randomized, double-blind study in patients undergoing abdominal hysterectomy to compare the effect of morphine 20 mg administered before operation with 10 mg at induction and 10 mg on closure of the peritoneum. Postoperative pain was assessed by visual analogue score (VAS) at rest and on movement and by total morphine consumption administered by patient-controlled analgesia (PCA). Wound sensitivity was assessed by von Frey pain thresholds. Both groups had similar morphine consumption, VAS scores and touch and pain thresholds, and in both, secondary hyperalgesia was prevented. Nausea and vomiting scores were higher in the 20-mg group. There was no significant difference between the two groups and neither regimen appeared to offer obvious clinical advantages compared with a lower dose (10 mg) morphine analgesic strategy. Therefore, there may be a ceiling effect to the production of pre-emptive analgesia by morphine.

Ginsberg et al 2000

Assessment of the relative clinical utility of sufentanil and morphine administered by patient controlled analgesia pumps following abdominal hysterectomy.

Journal of Pharmaceutical Care in Pain and Symptom Control 2000;8(4):5–17.

The objective of this study was to compare clinical efficacy of two opioid analgesics postoperatively using Patient Controlled Analgesia (PCA). It was a randomized, double-blind study involving 43 women undergoing elective abdominal hysterectomy. Each patient received a loading dose of 0.04 mL/kg (0.04 mg/kg morphine or 0.1 [mu]g/kg sufentanil) which was administered up to a maximum of three doses. Analgesic efficacy was assessed using a visual analog scale of pain (VAS). The PCA pump was set to administer a maintenance dose of 0.02 mL/kg (0.02 mg/kg morphine or 0.05 [mu]g/kg sufentanil) with a lockout interval of 8 minutes in all patients. Drug use was recorded and the VAS for pain was recorded at first request for analgesia, at 10, 20, 30, and 60 minutes, and at 4, 20 and 24 hours thereafter. Patients required 9.2 +/- 4.4 [mu]g of sufentanil and 7.28 +/- 3.7 mg morphine as loading dose for adequate analgesia (p < 0.05). During the first hour, 7.13 +/- 3 mL (17.8 +/- 7.5 [mu]g) of sufentanil and 13.4 +/- 5.68 mg) of morphine were used (p < 0.05). At 24 hours, the opioid doses were 223 +/- 87 [mu]g of sufentanil and 58.8 +/- 24.3 mg of morphine were used (p <0.05). Sufentanil provided significantly better analgesia at 10, 20, 30 and 60 minutes than morphine (p < 0.05). The ratio of sufentanil to morphine necessary for adequate analgesia changed from 1:791 at one hour to 1:267 at 24 hours. All the above differences significantly different. Sufentanil provides more rapid onset of analgesia and a lower demand to delivery ratio than morphine. The ratio of the dose requirements of sufentanil to morphine changed over time being higher initially and decreasing over the next 24 hours.

The present study contrasted the pharmaco-economics and analgesic efficacy of intramuscular (i.m.) opioid treatment with a parenteral disposable patient-controlled analgesia (PCA) system in two groups of 20 female patients (ASA I-II, aged 35-69 years) scheduled for abdominal hysterectomy. The PCA group received a continuous infusion of 1.5 mg h-1 piritramide, a mu-opioid receptor agonist, with incremental doses of 1.5 mg (lock-out interval = 15 min). The i.m. group received 0.3 mg kg-1 piritramide i.m. when requested by the patient with a minimum interval of 5 h. Pain intensity, sedation and the functional recovery of the patients were followed for 72 h post-operatively. The sum of pain intensity differences (SPID) was used as a measure of analgesic efficiency. Equipment and drug costs, and the demand on nursing time were recorded over 3 days post-operatively. The costs of PCA and i.m. therapies per patient were used to calculate the cost-benefit (cost of treatment vs. nursing time) and cost-effectiveness (cost of treatment vs. SPID) analyses. Both treatments initially provided comparable analgesia, but PCA was more efficient after 16 h and significantly reduced nursing time for pain treatment (PCA = 61 +/- 4 min, i.m. = 88 +/- 5 min; P < 0.001). Functional recovery was not different for either treatment. Cost analysis indicated a better cost-benefit ratio for the i.m. treatment (0.35 vs. 1.1 for PCA treatment), but a similar cost-effectiveness for both treatments (PCA = 1.9 Belgian Francs (BEF) unit-1 SPID; i.m. = 1.7 BEF unit-1 SPID).

Thomas et al 1995

Psychological characteristics and the effectiveness of patient-controlled analgesia.

Thomas V, Heath M, Rose D, Flory P.

Br J Anaesth 1995;74(3):271–276.

We have evaluated the level of state and trait anxiety, neuroticism, extroversion and coping style as predictors of the effectiveness of patient-controlled analgesia (PCA) in 110 patients undergoing total abdominal hysterectomy. After operation patients were allocated to receive pain control with either PCA or i.m. injections (IMI). Pain was assessed using the short form McGill pain questionnaire at 6, 18 and 24 h after operation, and by recording the amount of analgesic consumed in the first 24 h after surgery. Both state anxiety and coping style were significant predictors of postoperative pain, irrespective of the method of analgesia used. Patients using PCA experienced significantly better pain control than those receiving IMI. However, it was those with high levels of state anxiety who experienced the greatest reduction in pain with PCA. In addition to achieving better pain control, patients who received PCA used significantly less analgesia and were discharged earlier than patients who received IMI.

BACKGROUND: Many studies have shown the efficacy of patient-controlled analgesia (PCA). However, it is not clear whether PCA has clinical or economic benefits in addition to efficient analgesia. The current study was designed to evaluate these issues by comparing PCA with regularly administered intramuscular injections of opioids after hysterectomy. METHODS: This prospective study included 126 patients who underwent abdominal hysterectomy and were randomly assigned to receive PCA or regularly timed intramuscular injections of morphine during a period of 48 h. Doses were adjusted to provide satisfactory analgesia in both treatment groups. Pain at rest and with movement, functional recovery, drug side effects, and patient satisfaction were measured using rating scales and questionnaires. The costs of PCA and intramuscular therapy were calculated based on personnel time and drug and material requirements. RESULTS: Comparable analgesia was observed with the two treatment methods, with no significant differences in the incidence of side effects or patient satisfaction. The medication dosage had to be adjusted significantly more frequently in the intramuscular group than in the PCA patients. The PCA did not favor a faster recuperation time compared with intramuscular therapy in terms of times to ambulation, resumption of liquid and solid diet, passage of bowel gas, or hospital discharge. The results of the economic evaluation, which used a cost-minimization model and sensitivity analyses, showed that PCA was more costly than regular intramuscular injections despite the fact that no costs for the pump were included in the analyses. Cost differences in nursing time favoring PCA were offset by drug and material costs associated with this type of treatment. CONCLUSIONS: Compared with regularly scheduled intramuscular dosing, PCA is more costly and does not have clinical advantages for pain management after hysterectomy. Because of the comparable outcomes, the general use of PCA in similar patients should be questioned.

El-Falaki et al 2000

Intravenous patient -controlled fentanyl with and without adaptive background infusion after abdominal hysterectomy.

El-Falaki MM, Abu-hassan KA.

Journal of the Bahrain Medical Society 2000;12(3):139–142.

This study was designed to investigate the post operative quality of analgesia, side effects, patient satisfaction and dose requirements by using intravenous patient controlled fentanyl with and without adaptive background infusion. A prospective study of 20 patients undergoing abdominal hysterectomy are included in the study and divided into two equal groups. Group I received simple patient controlled fentanyl, and Group II received patient controlled fentanyl with adaptive background infusion. Visual analogue score was used to assess the pain and satisfaction. The patients who were given a background infusion had better quality of analgesia and greater satisfaction. No serious side effects were detected with the adaptive background infusion.

Striebel et al 1993

Intranasal meperidine titration for postoperative pain relief.

Striebel WH, Malewicz J, Hermanns K, Castello R.

Anesth Analg 1993;76(5):1047–1051.

A prospective, randomized, double-blind study investigating the efficacy of intranasal meperidine as compared with intravenous (i.v.) administration for postoperative pain relief is described. The study was limited to the initial titration of pain relief during a 2-h period immediately after surgery. Sixty women having undergone a hysterectomy were studied. Initially and when complaining of a pain intensity > or = 40 on the 101-point numerical rating scale (NRS), 30 patients received 6 sprays (27 mg) meperidine intranasally and simultaneously 6 mL NaCl 0.9% i.v. (nasal group); another 30 patients received 6 sprays of NaCl 0.9% intranasally and 6 mL of a diluted meperidine solution (27 mg) i.v. (intravenous group). Patients already having a pain reduction < 40 on the 101-point NRS, received half of the above dose. Meperidine was repeated every 5 min until the patients were pain free or refused further analgesic. Before the onset of meperidine titration and at 5- to 10-min intervals for 2 h thereafter, pain was evaluated with a 101-point NRS and a verbal rating scale. Within 20 and 35 min the pain scores evaluated by the NRS and verbal rating scale decreased in the intravenous and nasal group to a median of zero. The total dose of meperidine was 76.5 mg (range, 40.5-135.0) in the intravenous group and 104.4 mg (range, 27-135.0) in the nasal group (P < 0.05). One patient in each group showed a brief decrease in arterial hemoglobin oxygen saturation to < 90%. No patient complained of pain or burning in the nose.(ABSTRACT TRUNCATED AT 250 WORDS)

Fell et al 1982

Fifty patients undergoing hysterectomy or cholecystectomy took part in a trail of postoperative analgesia provided by either intramuscular morphine or controlled-release morphine sulphate tablets orally. Respiratory function and plasma catecholamine concentrations were measured after operation and pain was assessed by using a linear analogue scoring method. Controlled-release morphine sulphate produced comparable pain relief with that of intramuscular morphine, and depression of respiratory function after operation was similar with the two analgesic regimens. The mean total dose of drug per patient given over 48 h to patients undergoing hysterectomy was 115 mg for morphine sulphate and 53 mg for morphine. Patients undergoing cholecystectomy received 130 mg morphine sulphate or 76 mg morphine. There was more sedation after operation in those patients undergoing hysterectomy who received morphine sulphate tablets. Morphine sulphate tablets produced satisfactory postoperative analgesia compared with intramuscular morphine: both regimens were acceptable to the patients.

Coetzee et al 1998

Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy.

Coetzee JF, van Loggerenberg H.

Br J Anaesth 1998;81(5):737–741.

Tramadol may cause awareness and EEG activation during anaesthesia. We compared tramadol with morphine, administered during wound-closure, surmising that tramadol may cause earlier awakening, more rapid recovery, less respiratory depression and equivalent pain relief. Forty patients received nitrous oxide-enflurane for abdominal surgery. At wound closure, patients received tramadol 3 mg kg-1 or morphine 0.2 mg kg-1 and end-tidal enflurane concentrations were maintained at 0.5 kPa until skin closure, whereupon anaesthesia was discontinued. Times to spontaneous respiration, awakening and orientation were similar in the two groups, as were blood-gas tensions, ventilatory frequency, pain scores and incidence of nausea. Half of each group required supplementary analgesia during their 90-min stay in the recovery room. P-deletion counts improved more rapidly in the tramadol group. This study confirms previous reports that tramadol did not antagonize the hypnotic effects of volatile anaesthetics. Tramadol, administered during operation, was as effective as morphine in providing postoperative analgesia while permitting more rapid psychomotor recovery.

Chui et al 1992

This double-blind randomised study compared postoperative analgesia after a loading regimen of methadone or morphine in thirty women undergoing abdominal hysterectomy. Methadone or morphine, 0.25 mg.kg-1, was given intravenously at induction of anaesthesia with further increments in the recovery room for analgesia if required. The mean (SD) total doses of methadone and morphine required were 0.43 (0.13) mg.kg-1 and 0.45 (0.15) mg.kg-1 respectively. Patients in the methadone group had lower pain scores in the subsequent 48 hours (P less than 0.001) and required less supplementary intramuscular opioids (P less than 0.001). Ten patients in the methadone group did not request any further opioid analgesics while all patients in the morphine group made at least two requests for opioids. The overall postoperative course was remembered as less painful by patients in the methadone group (P less than 0.001). There was no significant respiratory depression or excessive sedation in either group.

Knoche et al 1983

Clinical experimental studies of postoperative infusion analgesia

Knoche E, Dick W, Bowdler I, Gundlach G.

Clin Ther 1983;5(6):585–594.

Thirty postoperative patients, after undergoing abdominal hysterectomy and standard general anesthesia, were randomly allocated to three groups and received, in the recovery ward, a continuous infusion of either pentazocine, piritramide, or ketamine. The patients rated their pain on a 15-cm visual analog scale. Patients in group 1 received pentazocine. Mean dosage was 0.12 mg/kg/hr on the day of operation, 0.1 mg/kg/hr on the first postoperative day, and only 0.07 mg/kg/hr on the second postoperative day. Pentazocine blood levels averaged 50 micrograms/L. Patients in group 2 received piritramide. Mean dosage was 0.038 mg/kg/hr on the day of operation, 0.024 mg/kg/hr on the first postoperative day, and 0.019 mg/kg/hr on the second postoperative day. Blood levels of piritramide were not determined because no satisfactory assay is available. Patients in group 3 received ketamine. Mean dosage was 0.32 mg/kg/hr on the day of operation, 0.28 mg/kg/hr on the first postoperative day, and 0.29 mg/kg/hr on the second postoperative day. Ketamine blood levels ranged between 120 and 180 micrograms/L. None of the three analgesics caused any important hemodynamic or respiratory side effects. Pentazocine and piritramide were more effective analgesics than ketamine was. Ketamine also had a higher incidence of side effects

BACKGROUND: The usefulness of intravenous patient-controlled analgesia (PCA) with opioids for postoperative analgesia is not well defined. METHODS: We systematically searched (MEDLINE, EMBASE, Cochrane Library, bibliographies, any language, to January 2000) for randomised trials comparing opioid-based PCA with the same opioid given intramuscularly, intravenously, or subcutaneously. Weighted mean differences (WMD) for continuous data, relative risks (RR) and numbers-needed-to-treat (NNT) for dichotomous data were calculated with 95% confidence intervals (CI) using fixed and random effects models. RESULTS: Data from 32 trials were analysed: 22 (1139 patients) were with morphine, five (682) with pethidine, three (184) with piritramide, one (47) with nalbuphine and one (20) with tramadol. In three morphine and one pethidine trial (352 patients), more patients preferred PCA (89.7% vs. 65.8%, RR 1.41 (95%CI 1.11 to 1.80), NNT 4.2). Combined dichotomous data on pain intensity and relief, and the need for rescue analgesics from eight morphine, one pethidine, one piritramide, and one nalbuphine trial (691 patients), were in favour of PCA (RR 1.22 (1.00 to 1.50), NNT 8). In two morphine trials (152), pulmonary complications were more frequently prevented with PCA (100% vs. 93.3%, RR 1.07 (1.01 to 1.14), NNT 15). There was equivalence for cumulative opioid consumption, pain scores, duration of hospital stay, and opioid-related adverse effects. CONCLUSION: These trials provide some evidence that in the postoperative pain setting, PCA with opioids, compared with conventional opioid treatment, improve analgesia and decrease the risk of pulmonary complications, and that patients prefer them.

Stamer et al 1997

Tramadol in the management of post-operative pain: a double-blind, placebo- and active drug-controlled study.

Stamer UM, Maier C, Grond S, Veh-Schmidt B, Klaschik E, Lehmann KA.

Eur J Anaesthesiol 1997;14(6):646–654.

A double-blind, randomized, placebo- and drug-controlled study in which the analgesic efficacy and safety of intravenous (i.v.) tramadol in patients with post-operative pain is reported. One hundred and eighty patients recovering from gynaecological or abdominal surgery were assigned to one of three treatment groups. After titration of an individual loading dose, patients could self-administer tramadol 20 mg, morphine 2 mg or placebo using a patient-controlled analgesia (PCA) device throughout a 48-h period. Criteria of efficacy were a decrease in pain intensity within the first 30 min of at least 20 on a visual analogue scale (VAS) (0 denotes no pain, 100 worst pain imaginable) and satisfactory analgesia in the patient's opinion during the study period. Patients treated with tramadol, morphine and placebo were assessed as responders at 66.7%, 75.0% and 18.3% (P < 0.0001). VAS after the initial bolus were 39.2 +/- 22.1, 35.9 +/- 21.6 and 50.0 +/- 24.2 (P = 0.002), the initial loading dose amounted to tramadol 144.9 +/- 51.2 mg, morphine 12.3 +/- 5.1 mg and placebo 17.2 +/- 4.9 mL. No serious opioid-related adverse events occurred in the patients given tramadol while two patients given morphine developed an impaired respiratory rate and a decreased oxygen saturation to 80% or less. Tramadol proved to be efficacious for PCA treatment of post-operative pain following gynaecological and abdominal surgery.

McQuay H et al 2003

BACKGROUND AND OBJECTIVE: Trials in acute postoperative pain are usually small. Pooling homogenous data from a number of trials in a meta-analysis enables a truer estimate of efficacy. The aims of the present meta-analysis were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen (paracetamol) in acute postoperative pain, and to demonstrate the efficacy of the combination formulation compared with its components. METHODS: Individual data from > 1400 adult dental or gynaecologic/orthopaedic patients with moderate-to-severe pain were taken from seven randomised, double-blind, placebo controlled trials of tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) with identical methods. The primary outcome measure was the number of patients needed to be treated (NNT) for one patient to obtain at least 50% pain relief. Information on adverse effects was also collected and the number needed to harm (NNH) was estimated. RESULTS: The tramadol/acetaminophen combination was more effective than either of its two components administered alone. For dental patients, who formed the bulk of the population, the combination formulation also had a significantly lower (better) NNT (approximately 3) than the components al one (approximately 8-12), comparable to ibuprofen 400 mg. The adverse effects associated with tramadol/acetaminophen were similar to those associated with the components alone. The commonest were dizziness, drowsiness, nausea, vomiting and headache. CONCLUSIONS: Meta-analysis confirmed the analgesic superiority of the combination treatment over its components, without additional toxicity. Combination analgesic formulations are an important and effective means of pain relief, and should prove useful in treating elderly and other groups of patients who often cannot tolerate non-steroidal anti-inflammatory drugs, including the newer COX-2 inhibitors.

Varrassi et al 1999

A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery.

We assessed the relative morphine consumption in a combined analgesic regimen (on-demand morphine plus the nonopioids propacetamol or ketorolac) after gynecologic surgery. Two hundred women randomly received two i.v. doses of propacetamol 2 g or ketorolac 30 mg in a double-blinded, double-dummy trial. Patients were monitored for 12 h, and the following efficacy variables were assessed: total dose of morphine, pain intensity, and global efficacy. Safety and tolerability were evaluated by the occurrence of adverse events, especially the presence and intensity of gastrointestinal symptoms. Hemostatic variables were measured 30 and 60 min after the first infusion; arterial blood pressure, heart and respiratory rates, sedation scores, and renal and hepatic function were also assessed. Total morphine requirements were not significantly different between the propacetamol (10.6 +/- 4.8 mg) and ketorolac (10.2 +/- 4.4 mg) groups. The evolution of pain intensity and the global efficacy also showed similar patterns in the two groups: 70.2% of patients in the propacetamol group rated the efficacy as "good/ excellent" compared with 68.2% in the ketorolac group. There were no clinically significant changes in vital signs or laboratory values and no observed differences between the two groups, although ketorolac slightly, but not significantly, prolonged the bleeding time. Epigastric pain was present in 9% and 15% of patients receiving propacetamol and ketorolac, respectively. There were two adverse events in the propacetamol group and four in the ketorolac group. Propacetamol demonstrates an efficacy similar to that of ketorolac and has an excellent tolerability after gynecologic surgery. IMPLICATIONS: Propacetamol and ketorolac, combined with patient-controlled analgesia morphine, show similar analgesic efficacy after gynecologic surgery. Morphine consumption and pain scores were comparable in the two studied groups. Propacetamol is as effective as ketorolac and has an excellent tolerability after gynecologic surgery.

Rømsing et al 2002

Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia.

Rømsing J, Moiniche S, Dahl JB.

Br J Anaesth 2002;88(2):215–226.

BACKGROUND: We have reviewed the analgesic efficacies of rectal and parenteral paracetamol and tested the evidence for a possible additive analgesic effect of the combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) in postoperative pain. METHODS: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia. RESULTS: Eight studies compared rectal paracetamol with placebo. One study of single-dose administration of rectal paracetamol 40–60 mg/kg and three studies of repeat dosing with 14–20 mg/kg showed significant analgesic efficacy, while studies of a single dose of 10–20 mg/kg were negative. Ten studies compared parenteral paracetamol with placebo and eight studies showed improved pain relief with paracetamol. Of the nine studies comparing paracetamol with a combination of paracetamol and an NSAID, six studies showed improved pain relief for the combination while only two of the six studies comparing an NSAID with a combination of an NSAID and paracetamol showed improved pain relief for the combination. CONCLUSIONS: Considering the few studies available, evidence was found of a clinically relevant analgesic effect of rectal and parenteral paracetamol. Concurrent use of paracetamol and an NSAID was superior to paracetamol alone but no evidence was found of superior analgesic effect of the combination compared with the NSAID alone.

Montgomery et al 1996

Morphine consumption in patients receiving rectal paracetamol and diclofenac alone and in combination.

Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR.

Br J Anaesth 1996;77(4):445–447.

Paracetamol and diclofenac have different mechanisms of action, and the combination may be more effective than each drug used alone in treating postoperative pain. In a double-blind, controlled design, we studied 60 patients undergoing elective abdominal gynaecological surgery, who received suppositories of paracetamol 1.5 g, diclofenac 100 mg or a combination of the two before the start of surgery. Patients received morphine in the intraoperative period, and cumulative morphine use from a patient-controlled analgesia system was recorded to measure the analgesic effect of the suppositories. Morphine consumption was greatest in the group that received paracetamol alone and lowest in the group given the combination (P < 0.01). There was no difference in the incidence of morphine-related side effects between the groups. We conclude that a diclofenac-paracetamol combination reduced the amount of morphine used compared with paracetamol alone.

Jahangir et al 1993

Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine.

Jahangir SM, Islam F, Aziz L.

Anesth Analg 1993;76(1):45–49.

Narcotics commonly used for postoperative analgesia may release histamine and cause bronchospasm in asthmatics. Ketamine, on the other hand, provides analgesia and has the additional advantage of preventing and relieving bronchospasm. We therefore delivered subanesthetic doses of ketamine in combination with midazolam (5.88-6.42 micrograms.kg-1.min-1 and 1.17-1.28 micrograms.kg-1.min-1, respectively), via an infusion for postoperative analgesia after elective abdominal hysterectomy in patients with asthma. Data were compared with those from a similar group of patients receiving conventional intramuscular meperidine. A significant degree and earlier onset of analgesia (P < 0.05) was achieved in the ketamine group. For other variables no significant difference was observed between the groups (P > 0.05). Ketamine-midazolam infusion can thus provide a safe alternative to the usual parenteral narcotic therapy in asthmatics, in terms of analgesia and patient acceptability.

Fry 1979

Relief of pain after surgery. A comparison of sublingual buprenorphine and intramuscular papaveretum.

Fry EN.

Anaesthesia 1979;34(6):549–551.

Sublingual buprenorphine (0.4 mg) and intramuscular papaveretum (20 mg) were compared in sixty patients after abdominal hysterectomy. Though slower in onset of effect the sublingual tablets proved effective for pain relief and appeared to have a longer duration of action. The only side-effects of note were nausea and vomiting which occurred after both treatments. Haloperidol was tried as a long acting antiemetic and appeared successful.

Egan et al 1992

Self-administration of midazolam for postoperative anxiety: a double blinded study.

Egan KJ, Ready LB, Nessly M, Greer BE.

Pain 1992;49(1):3–8.

Anxiety is almost inevitably present in patients facing surgery. The optimal management of postoperative pain requires the acknowledgement of perioperative anxiety and the inclusion of pharmacological and/or non-pharmacological means of alleviating the fear and worry inherent in the surgical experience. In a double-blind randomized design, 39 patients undergoing total abdominal hysterectomies were given postoperative access to a standard patient-controlled analgesia (PCA) morphine pump for pain and a PCA pump dispensing either low-dose midazolam or saline for anxiety. Measures of anxiety and pain were completed pre-operatively and for 2 days postoperatively. Utilization of morphine and 'anxiolytic agent' were recorded. Analysis of covariance was applied to the data to control for the imbalance of cancer patients between the 2 groups. While both groups of patients chose to utilize their 'anxiety pump' throughout the study, those patients receiving midazolam had significantly lower postoperative Spielberger State Anxiety scores and visual analogue scale anxiety scores. Patient-controlled midazolam in doses used in this study were safe and effective in managing anxiety but did not influence pain scores or the amount of PCA morphine patients used. Pre-operative levels of depression were significantly associated with postoperative pain levels independent of treatment group or cancer diagnosis.

Tiengo et al 1987

Clomipramine compared with pentazocine as a unique treatment in postoperative pain.

Tiengo M, Pagnoni B, Calmi A, Calza L, Rigoli M, Braga P, Panerai

Int J Clin Pharmacol Res 1987;7(2):141–143.

Forty patients who underwent laparotomy for hysterectomy were administered either clomipramine or pentazocine for the treatment of postoperative pain. Both drugs were similarly effective during the eight hours of observation. The results of this study indicate that clomipramine, often used in chronic pain as an adjuvant drug, exerts as well as analgesic effect in acute pain.

Buggy et al 2003

Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain.

Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ.

Pain 2003;106(1–2):169.

We have evaluated the efficacy of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive constituent of cannabis, in postoperative pain. In a randomized double-blind, placebo-controlled, single-dose trial, we investigated 40 women undergoing elective abdominal hysterectomy. Randomization took place when postoperative patient-controlled analgesia was discontinued on the second postoperative day. When patients requested further analgesia, they received a single, identical capsule of either oral delta-9-THC 5 mg (n=20) or placebo (n=20) in a double-blind fashion. The primary outcome measure was summed pain intensity difference (SPID) at 6 h after administration of study medication derived from visual analogue pain scores on movement and at rest. Secondary outcome measures were time to rescue medication and adverse effects of study medication. Mean (SD) VAS pain scores before medication in the placebo and delta-9-THC groups were 6.3(2.6) and 6.4(1.3)cm on movement, and 3.2(1.9) and 3.3(0.9) on rest, respectively. There were no significant differences in mean (95% confidence interval of the difference) SPID at 6 h between the groups [placebo 7.9, delta-9-THC 4.3(-1.8 to 9.0)cm h on movement; placebo 8.8, delta-9-THC 4.9(-0.2 to 8.1)cm h at rest] and time to rescue analgesia [placebo 217, delta-9-THC 163(-22 to 130)min]. Increased awareness of surroundings was reported more frequently in patients receiving delta-9-THC (40 vs 5%, P=0.04). There were no other significant differences with respect to adverse events. This study demonstrates no evidence of an analgesic effect of orally administered delta-9-THC 5 mg in postoperative pain in humans.

Gan et al 1997

Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate.

Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R.

Anesthesiology 1997;87(5):1075–1081.

BACKGROUND: A naloxone infusion is effective in reducing epidural and intrathecal opioid-related side effects. The use of naloxone infusion concomitant with intravenous morphine patient-controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemic opioid effect. The authors compared the incidence of morphine-related side effects and the quality of analgesia from two small doses of naloxone infusion. METHODS: Sixty patients classified as American Society of Anesthesiologists physical status 1, 2, or 3 who were scheduled for total abdominal hysterectomies were enrolled in the study. Patients received a standardized general anesthetic. In the postanesthetic care unit, patients received morphine as a PCA. They were randomized to receive either 0.25 microg x kg(-1) x h(-1) naloxone (low dose), 1 microg x kg(-1) x h(-1) (high dose), or saline (placebo) as a continuous infusion. Verbal rating scores for pain, nausea, vomiting, and pruritus; sedation scores; requests for antiemetic; and morphine use were recorded for 24 h. Blood pressure, respiratory rate, and oxyhemoglobin saturation were also monitored. RESULTS: Sixty patients completed the study. Both naloxone doses were equally effective in reducing the incidence of nausea, vomiting, and pruritus compared with placebo (P < 0.05 by the chi-squared test). There was no difference in the verbal rating scores for pain between the groups. The cumulative morphine use was the lowest in the low-dose group (42.3 +/- 24.1 mg; means +/- SD) compared with the placebo (59.1 +/- 27.4 mg) and high-dose groups (64.7 +/- 33.0 mg) at 24 h (P < 0.05 by analysis of variance). There was no incidence of respiratory depression (<8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. CONCLUSIONS: Naloxone is effective in preventing PCA opioid-related side effects. Naloxone infusion at 0.25 microg x kg(-1) x h(-1) not only attenuates these side effects but appears to reduce postoperative (beyond 4-8 h) opioid requirements. This dosing regimen can be prepared with 400 microg naloxone in 1,000 ml crystalloid given in 24 h to a patient weighing 70 kg.

OBJECTIVE: The aim of this study is to compare the effect on postoperative pain of epidural ropivacaine in combination with intravenous ketorolac with intravenous ketorolac alone following transabdominal hysterectomy. DESIGN: A multi-center, randomized, double-blind study was conducted in Thailand and the Philippines to assess postoperative pain management in 107 patients given ketorolac alone or in combination with epidural ropivacaine following transabdominal hysterectomy. Pain score was assessed using a 100-mm visual analogue pain scale (VAS). RESULTS: The VAS scores for pain on coughing and at rest were significantly better in the ropivacaine group. The number of patients who asked for morphine in addition was higher in the ketorolac group compared to the ropivacaine + ketorolac group. The time taken to carry out the first three ambulatory steps was similar for both the two treatment groups. A higher degree of motor block was observed in the ropivacaine group over time. The adverse events observed were similar in both groups. CONCLUSION: We demonstrated that epidural infusion of ropivacaine in addition with intravenous ketorolac gave superior pain relief at rest and on coughing in patients undergoing transabdominal hysterectomy when compared to the group receiving intravenous ketorolac alone.

Madej et al 1992

We have examined postoperative pain in patients allocated randomly to receive extradural bolus diamorphine 3.6 mg, extradural infusion of 0.15% bupivacaine with 0.01% diamorphine or patient-controlled i.v. administration of diamorphine at a maximum rate of 1 mg per 5 min, after total abdominal hysterectomy. Extradural infusion analgesia produced the smallest pain scores from 12 to 24 h after surgery (P < 0.05). More patients in the extradural infusion group were moderately hypoxaemic (SpO2 < 90% > 12 min h-1) after operation, compared with the two other groups (P < 0.05). The group using patient-controlled analgesia received more diamorphine and suffered a greater incidence of emetic sequelae (P < 0.05).

Postoperative analgesia provided by epidurally administered sufentanil and/or morphine was evaluated in 45 patients recovering from major gynecologic surgery. At the first complaint of pain in the Postanesthesia Care Unit, patients received a single epidural bolus of 30 micrograms sufentanil (group A), 5 mg morphine (group B), or 30 micrograms sufentanil plus 3 mg morphine (group C) in a randomized blinded fashion. Analgesic efficacy was assessed throughout the 24-h study period with 10-cm visual analog scales. The need for additional postoperative analgesia (patient-controlled analgesia, 1 mg of morphine every 6 min as necessary) and the incidence of adverse effects were also assessed. Patients receiving sufentanil (groups A and C) had significantly faster onset of analgesia than did patients given morphine alone (group B, P less than 0.05). Group B subjects experienced the longest duration of analgesia (B vs A and C, P less than 0.05) and required significantly less patient-controlled analgesia (morphine) than patients in group A (P less than 0.05). No patient developed clinically significant respiratory depression or excessive sedation, and there were no intergroup differences in incidence of pruritus or nausea (P value not significant). The data indicate that a mixture of sufentanil and morphine provides either a more rapid onset of epidural analgesia or reduced patient-controlled analgesia narcotic requirement than respective doses of each agent administered alone.

Thoren et al 1989

Effects of epidural bupivacaine and epidural morphine on bowel function and pain after hysterectomy.

Thoren T, Sundberg A, Wattwil M, Garvill JE, Jurgensen U.

Acta Anaesthesiol Scand 1989;33(2):181–185.

A comparison was made of the effects of continuous epidural analgesia with bupivacaine and intermittent epidural morphine on bowel function after abdominal hysterectomy. The duration of postoperative ileus was assessed as the time from the end of operation to the first postoperative passage of flatus and feces. Twenty-two patients were randomly allocated to two equal groups. An "epidural morphine" group received general anesthesia and epidural morphine for postoperative pain relief, and an "epidural bupivacaine" group was given combined general anesthesia and epidural anesthesia with 0.5% bupivacaine intraoperatively and epidural analgesia with 0.25% bupivacaine postoperatively. Epidural morphine or bupivacaine was given for 42 h postoperatively. Pain intensity (visual analog scale) was low in both groups, but lower (P less than 0.05) in the epidural bupivacaine group. The time to first passage of flatus was 22 +/- 16 h in the epidural bupivacaine group and 56 +/- 22 h in the epidural morphine group (P less than 0.001). The time to first postoperative passage of feces was shorter (P less than 0.05) in the former than in the latter 57 +/- 44 h vs 92 +/- 22 h). The patients of the epidural bupivacaine group started intake of oral fluids earlier (P less than 0.01) and to a greater extent (P less than 0.05) than those in the epidural morphine group. It is concluded that the duration of postoperative ileus after hysterectomy is shorter when epidural bupivacaine is given for postoperative pain relief than when this is achieved by epidural morphine.

Choi et al 2000

PURPOSE: To determine whether epidural naloxone preserved analgesia while minimizing side effects caused by epidural morphine. METHODS: Eighty patients undergoing combined epidural and general anesthesia for hysterectomy were randomly assigned to one of four groups. All received 2 mg epidural morphine bolus one hour before the end of surgery and a continuous epidural infusion was started containing 4 mg morphine in 100 ml bupivacaine 0.125% with either no naloxone (Group 1, n=20), 0.083 µg/kg/hr of naloxone (Group 2, n=20), 0.125 µg/kg/hr of naloxone (Group 3, n=20) or 0.167 µg/kg/hr of naloxone (Group 4, n=20). Analgesia and side effects were evaluated by blinded observers. RESULTS: The combination of epidural morphine and bupivacaine provided good analgesia. Eight hours after the end of surgery, the pain score in the group receiving the highest dose of naloxone was lower than in the control group (VAS 1.2 vs. 2.0, p<0.05) but there was less pruritus in the high-dose naloxone group (itching score 1.3 vs. 1.9, p<0.05). Pain scores were no different in any of the naloxone groups from the control group. Itching was less in both of the higher dose naloxone groups (p<0.05 at 8, 16, and 32 hours). The incidence of vomiting in the control group was 40% vs. 5% for high dose naloxone group (p<0.05). CONCLUSIONS: Epidural naloxone reduced morphine-induced side effects in dose-dependent fashion without reversal of the analgesic effect.

Liu at al 1997b

Clinical study of epidural analgesia with clonidine and sumatriptan in posthysterectomy.

Liu Z, Tian Y, Zhang C, Jin S.

J Tongji Med Univ 1997b;17(3):172–176.

A clinical study was conducted to compare the analgesic effect of clonidine with those of sumatriptan and their mixture and their effects on hemodynamics. 40 patients undergoing elective total hysterectomy were randomly divided into 4 groups in terms of the epidurally administered drugs with 10 patients in each group (group C1: clonidine 150 micrograms, group C2: clonidine 75 micrograms, group S: sumatriptan 6 mg and group S + C: clonidine 75 micrograms + sumatriptan 3 mg). MAP, HR, SpO2, VT VAS, VRS and ePDT were measured in the initial 4 h. The demographic data and the doses of intraoperative local anesthetics among the 4 groups were not statistically different. It was found that no significant difference in the pre- and postadministration values of HR, SpO2 and VT. A obvious reduction of MAP appeared in the groups of C1 and C2, but in the other groups the hemodynamical parameters were stable. The groups of C1, C2 and S + C showed significant increase in VAS and VRS, along with increase of ePDT when compared with the pre-drug level. There was no obvious alteration in group S after the drug administration. It was concluded that (1) single use of sumatriptan is ineffective in the dose given in this study; (2) small dose (150 micrograms and 75 micrograms) of clonidine has epidurally analgesic effects; (3) combined use of sumatriptan and clonidine is an acceptable way in epidural analgesia, in terms of its analgesic effect and hemodynamic changes.

We have investigated the effect of 24-h postoperative continuous epidural infusion of 0.2% ropivacaine or 0.2% bupivacaine 8 ml h-1 on pain, request for supplementary analgesics, motor block and gastrointestinal function, in a double-blind, randomized study in 60 patients undergoing open hysterectomy. There were no significant differences between groups in pain, number of patients requesting supplementary analgesics, motor block, ability to walk or time to first flatus or stool. In the subgroup of patients who received supplementary analgesics, patients in the ropivacaine group received significantly more ketorolac than patients in the bupivacaine group. Time to discharge from hospital was similar with ropivacaine and bupivacaine.

Peat et al 1989

A double-blind comparison of epidural ketamine and diamorphine for postoperative analgesia.

Peat SJ, Bras P, Hanna MH.

Anaesthesia 1989;44(7):555–558.

Twenty patients who had abdominal hysterectomy under general anaesthesia were randomly assigned to receive either epidural ketamine (30 mg), or epidural diamorphine (5 mg) peri-operatively and on first request for analgesia. Failure to obtain satisfactory analgesia with one of the agents was treated by epidural administration of the other. Pain was assessed by an independent observer, and by the patient using a visual analogue scale. The mean (SD) pain score on recovery from general anaesthesia, on a scale of 0-4, was 2.9 (1.2) for the ketamine group and 1.0 (1.0) for the diamorphine group (p less than 0.01). The mean (SD) time to first request for analgesia was 272 (206) and 72 (41) minutes in the diamorphine and ketamine groups respectively (p less than 0.01). All patients in the diamorphine group obtained adequate analgesia, but all patients in the ketamine group were changed to epidural diamorphine. Epidural ketamine does not appear to be a sufficiently effective alternative to epidural diamorphine for routine use in postoperative pain.

In a randomized, double-blind study of 40 patients undergoing total abdominal hysterectomy, we have compared continuous subcutaneous infusion (CSCI) of morphine with discontinuous extradural injection of morphine for postoperative analgesia at rest and during cough. The CSCI group received a bolus of morphine 0.1 mg kg-1 i.v. at the end of the operation and continued with s.c. infusion of morphine 30 micrograms kg-1 h-1. The extradural group received morphine 4 mg extradurally at 0, 2, 10 and 18 h after operation. Pain and side effects were evaluated at 2, 4, 8, 12 and 24 h after operation. In the extradural group, significantly smaller pain-scores were observed both at rest and during cough compared with the CSCI group. No significant difference was observed between the groups regarding supplementary doses of morphine, peak expiratory flow values or side effects. We conclude that morphine by CSCI is not as effective as morphine injected extradurally. However, CSCI seems to provide simple and relatively effective analgesia with a low rate of side effects.

We examined if patient-controlled analgesia (PCA) with i.v. morphine provided comparable postoperative analgesia after hysterectomy as extradural morphine, without increasing the incidence of side effects. The study (n = 40) was randomized and double-blind. An extradural catheter was inserted before surgery and anaesthesia was standardized. The extradural group received extradural morphine 0.06 mg kg-1 by the end of surgery and a second dose 6 h later. The i.v. group received an i.v. infusion of morphine 0.2 mg kg-1 after surgery. PCA with morphine 0.04 mg kg-1 i.v. was used in both groups. Pain relief (VAS), side effects and cognitive functions were evaluated for 18 h. Plasma samples were obtained for analysis of morphine concentrations. Mean consumption of PCA morphine was 2.4 mg h-1 for the i.v. group and 1 mg h-1 for the extradural group. Despite unlimited access to morphine, the i.v. group had higher VAS scores as the extradural group (P < 0.001). Plasma concentrations of morphine varied 8-10-fold in both groups. In the i.v. group itching, tiredness, blurred vision and vertigo correlated with cumulative consumption of i.v. morphine whereas in the extradural group this correlation existed only for tiredness. Both groups showed reduced ability to perform tests of cognitive function, indicating a central effect of both i.v. and extradural morphine, despite markedly lower plasma morphine concentrations in the extradural group.

Camu et al 1991

Alfentanil infusion for postoperative pain: a comparison of epidural and intravenous routes.

Camu F, Debucquoy F.

Anesthesiology 1991;75(2):171–178.

The efficacy of intravenous (iv) and epidural infusions of alfentanil for postoperative pain relief was investigated in 24 patients (ASA physical status 1-2) who were scheduled for abdominal hysterectomy. The patients were allocated randomly to receive either epidural or iv alfentanil. In both groups, a loading dose of 15 micrograms.kg-1 was administered, followed by a constant rate infusion of 18 micrograms.kg-1.h-1 alfentanil for 20 h. Both routes provided similar degrees of analgesia; however, analgesia occurred earlier in the intravenously treated group (P less than 0.03). Mean plasma alfentanil concentrations (Cps) varied between 42 and 82 ng.ml-1 in the iv group and 23 and 68 ng.ml-1 in the epidural group, with higher concentrations in the iv group for the first 60 min only (P less than 0.01). Cps increased with infusion time, suggesting accumulation of alfentanil. After infusion ended, pain recurred at the same time in both groups, whereas the alfentanil Cps still were greater than 45 ng/ml. Postoperative epinephrine concentrations decreased after 60 min of infusion (P less than 0.02), whereas, after 6 h, cortisol levels decreased to preoperative values. Norepinephrine concentrations decreased only slightly. The only clinically meaningful effect on vital signs that occurred was an abrupt reduction of respiratory rate after the iv loading dose. PaCO2 increased to the same extent in both groups during the first 15 min only. The incidence of opioid-related side effects was similar in both groups. These results suggest that the iv and epidural routes were equally effective for providing postoperative pain control and controlling the postoperative response to surgical stress.

Lund et al 1989

Comparison of the effects of extradural clonidine with those of morphine on postoperative pain, stress responses, cardiopulmonary function and motor and sensory block.

Lund C, Qvitzau S, Greulich A, Hjortso NC, Kehlet H.

Br J Anaesth 1989;63(5):516–519.

We have examined the effects of extradural clonidine 150 micrograms or morphine 4 mg on postoperative pain, stress responses, cardiopulmonary function and motor and sensory block in a double-blind, randomized study in 20 patients undergoing hysterectomy with general anaesthesia. Observations were made for 6 h after each patient's first request for analgesia. Clonidine provided greater pain relief than morphine only for the first 2 h of observation (P less than 0.001). Plasma cortisol concentrations decreased to a greater extent (P less than 0.05) with morphine, while plasma glucose concentration increased by a similar extent in both groups. After clonidine, mean arterial pressure decreased from 100 (SEM 3) mm Hg to 70 (3) mm Hg (P less than 0.05), but there was no change after morphine. There were no significant changes in heart rate, pulmonary function (FEV1), motor function or sensory analgesia to touch, temperature and pinprick in both groups. Additional systemic opioids were required by five and six patients in the clonidine and morphine groups, respectively.

BACKGROUND: Gastrointestinal paralysis, nausea and vomiting, and pain, are major clinical problems following abdominal surgery. Anaesthetic and analgesic techniques that reduce pain and postoperative nausea and vomiting (PONV), and prevent or reduce postoperative ileus, may reduce postoperative morbidity, duration of hospitalisation and hospital costs. OBJECTIVES: To compare effects of postoperative epidural local anaesthetic with regimens based on systemic or epidural opioids, on postoperative gastrointestinal function, postoperative pain, PONV and surgical/anaesthetic complications. SEARCH STRATEGY: Trials were identified by computerised searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE and by checking the reference lists of trials and review articles. SELECTION CRITERIA: Randomised controlled trials comparing the effects of postoperative epidural local anaesthetic with systemic or epidural opioids. DATA COLLECTION AND ANALYSIS: Collected data included treatment in active (local anaesthetic) and control (opioid based) groups, time to first postoperative stool, time to first postoperative flatus, gastric emptying measured by the paracetamol absorption test, duration of the passage of barium sulphate, pain assessments, use of supplementary analgesics, nausea, vomiting and surgical/anaesthetic complications. MAIN RESULTS: Most studies in this review involved a small number of patients. Furthermore half of the studies indicated a poor level of methodology in particular regarding blinding and report of withdrawals. Heterogeneity of included studies was substantial. Results consistently showed reduced time to return of gastrointestinal function in the epidural local anaesthetic group compared with groups receiving systemic or epidural opioid (37 hours and 24 hours, respectively). Postoperative pain was comparable. Two studies compared the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on gastrointestinal function. One study favoured epidural local anaesthetic and one study was indifferent. A meta analysis of five of eight studies comparing the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on postoperative pain, yielded a reduction in VAS pain scores (0-100 mm) on the first postoperative day of 15 mm, in favour of the combination. No significant differences in PONV were observed between epidural local anaesthetic and opioid based regimens. REVIEWER'S CONCLUSIONS: Administration of epidural local anaesthetics to patients undergoing laparotomy reduce gastrointestinal paralysis compared with systemic or epidural opioids, with comparable postoperative pain relief. Addition of opioid to epidural local anaesthetic may provide superior postoperative analgesia compared with epidural local anaesthetics alone. The effect of additional epidural opioid on gastrointestinal function is so far unsettled. Randomized, controlled trials comparing the effect of combinations of epidural local anaesthetic and opioid with epidural local anaesthetic alone on postoperative gastrointestinal function and pain are warranted.

BACKGROUND AND OBJECTIVES: It is well known that wound infiltration with local anesthetic can reduce postoperative pain in various degrees and with very few side effects. A previous study showed better analgesic effect when local anesthetic was applied in the subfascial, rather than the subcutaneous, layer. The present study investigated the effect of frequent bolus injections of bupivacaine (15 mL 2.5 mg/mL) preperitoneally through catheters placed intraoperatively in women who had undergone hysterectomy. METHODS: Postoperative pain and analgesic requirements were studied in a double-blind randomized trial including 41 patients. During surgery, the patients were randomized to one of two groups, and the investigators were blinded. Prior to closure of the peritoneum, the surgeon placed a catheter between the muscle layer and the peritoneum on each side of the wound. One group (n = 22) received bupivacaine (15 mL 2.5 mg/mL) every 4 hours for 48 hours via each catheter starting in the operating room. The placebo group (n = 19) received saline in a like manner. Postoperative pain was evaluated using a visual analog scale (VAS) and verbal rating scale (VRS) twice a day for 2 days at rest and on movement. Requirements of supplementary analgesics were monitored, as was wound infection after discharge. RESULTS: Bupivacaine administered preperitoneally did not improve analgesia at rest, during coughing, or during mobilization compared with saline. No difference between the groups was found regarding analgesic requirements. No complications of postoperative wound healing or toxic side effects were seen. CONCLUSION: Bolus injections of bupivacaine through intraoperative placed catheters did not improve analgesia postoperatively compared with saline injections.

Zohar et al 2001

The analgesic efficacy of patient-controlled bupivacaine wound instillation after total abdominal hysterectomy with bilateral salpingo-oophorectomy.

Zohar E, Fredman B, Phillipov A, Jedeikin R, Shapiro A.

Anesth Analg 2001;93(2):482–487.

To assess the effect of local anesthetic wound instillation on visceral and somatic pain, we studied 36 patients undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy. A standard general anesthetic was administered. On completion of the operation, a multiorifice 20-gauge epidural catheter was placed above the superficial abdominal fascia such that the tip was at the midpoint of the surgical wound. After surgery, either bupivacaine 0.25% (Bupivacaine group) or sterile water (Control group) was administered via a patient-controlled analgesia device programmed to deliver 9.0 mL with a 60-min lockout interval. During the first 6 h after surgery, rescue IV morphine (2 mg) was administered every 10 min until a visual analog scale score of <30 mm was achieved. Thereafter, on patient request, rescue meperidine 1 mg/kg IM was administered. When compared with the Control group, significantly (P < 0.001) less rescue analgesia was administered to patients in the Bupivacaine group. Rescue morphine administered during the first 6 h after surgery was 6 +/- 4 mg versus 12 +/- 6 mg (P < 0.001) for the Bupivacaine and Control groups, respectively. Rescue meperidine administered was 29 +/- 37 mg versus 95 +/- 36 mg (P < 0.001) for the Bupivacaine and Control groups, respectively. Nausea and antiemetic drug administration was significantly (P = 0.003) less in the Bupivacaine group. Pain scores were similar between the groups. Patient satisfaction was significantly (P = 0.04) more in the Bupivacaine group. We conclude that bupivacaine wound instillation decreases opioid requirements and nausea in the first 24 h after total abdominal hysterectomy with bilateral salpingo-oophorectomy. IMPLICATIONS: Bupivacaine instillation via an electronic patient-controlled analgesia device provides effective analgesia after total abdominal hysterectomy with bilateral salpingo-oophorectomy.

Taylor et al 1998

The effect of music in the postanesthesia care unit on pain levels in women who have had abdominal hysterectomies.

Taylor LK, Kuttler KL, Parks TA, Milton D.

J Perianesth Nurs 1998;13(2):88–94.

Management of pain in the immediate postoperative period is a major concern of postanesthesia nurses. Music is a nursing intervention with the potential to decrease patient perception of pain in the PACU. The purpose of this study was to examine the effect of the use of music on the level of patient pain in the immediate postoperative period. A quasi-experimental study design was used with three study groups. All patients scheduled for elective abdominal hysterectomies using a general anesthesia technique were eligible for participation in the study. The setting is a PACU in a community hospital in a suburban area. Subjects were asked to rate their pain level every 15 minutes while in the PACU using two valid and reliable measures, a verbal pain rating scale and a graphic numeric pain intensity scale. Repeated measures of analysis of variance showed no differences in level of pain between groups or over time.

OBJECTIVE: This study was conducted to evaluate the analgesic efficacy of meloxicam in abdominal hysterectomy. METHODS: The study population consisted of 52 patients scheduled for total abdominal hysterectomy who were ASA 1 or 2 physical status female. Patients were allocated randomly to receive orally either 15 mg of meloxicam (Group M, n = 27) or placebo (Group P, n = 25) before anaesthesia induction. After intravenous administration of 1.5 mg kg (-1) of tramadol, anaesthesia was induced with an intravenous loading dose of 1-2 mg kg(-1) propofol. Anaesthesia was maintained on intravenous infusion of propofol at 6-12 mg kg(-1) h plus tramadol at 1 mg kg(-1) h(-1), vecuronium, and a 2:1 nitrous oxide-oxygen mixture. RESULTS: The relative propofol consumption was lower in Group M than in Group P, (p < 0.05). The time for analgesic rescue decreased in the order Group M > Group P (p < 0.01). The degree of sedation was similar between the groups (p > 0.05) and the visual analog scores (10-cm scale) and verbal rating scale data differences were present in the first 2 h only (p < 0.05). When side-effects were evaluated nausea and vomiting were found to be lower in group M than in group P (p < 0.05). CONCLUSION: Pre-emptive meloxicam provided better postoperative analgesia than placebo.

We designed this study to determine whether the administration of a preoperative dose of rofecoxib to patients undergoing abdominal hysterectomy would decrease patient-controlled analgesia (PCA) tramadol use or enhance analgesia. Sixty patients were randomized to receive either oral placebo or rofecoxib 50 mg 1 h before surgery. All patients received a standard anesthetic protocol. Intraoperative blood loss was determined. At the end of surgery, all patients received tramadol IV via a PCA-device. Pain scores, sedation scores, mean arterial blood pressure, heart rate, and peripheral oxygen saturation were assessed at 1, 2, 4, 6, 8, 12, and 24 h after surgery. Total and incremental tramadol consumption at the same times was recorded from the PCA-device. Antiemetic requirements and adverse effects were noted during the first postoperative 24 h. Duration of hospital stay was also recorded. The pain scores were significantly lower in the rofecoxib group compared with the placebo group at 6 times during the first 12 postoperative h (P < 0.05). The total consumption of tramadol (627 +/- 69 mg versus 535 +/- 45 mg; P < 0.05) and the incremental doses at 1, 2, 4, 6, 8, and 12 h after surgery were significantly more in the placebo group than in the rofecoxib group. There were no differences between groups in intraoperative blood loss, sedation scores, hemodynamic variables, peripheral oxygen saturation, antiemetic requirements, or adverse effects after surgery. The length of hospital stay was also similar in the groups. We conclude that the preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the opioid requirements in patients undergoing abdominal hysterectomy. IMPLICATIONS: This study was designed to determine whether the administration of a preoperative dose of rofecoxib to patients undergoing abdominal hysterectomy would decrease patient-controlled analgesia tramadol use or enhance analgesia. We conclude that the preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the opioid requirements in patients undergoing abdominal hysterectomy.

In this randomized, double blind placebo controlled study, the authors evaluated the effects of oral clonidine premedication on very low dose epidural morphine analgesia in 50 hysterectomy patients. Patients were randomized to receive a single oral clonidine 300 microg (n = 25) or a placebo (n = 25) 90 minutes before insertion of the epidural catheter. 3 ml of 2% lidocaine with adrenaline (5 microg ml(-1) mixed with 2 mg morphine were injected via epidural, followed by an additional volume of 2% lidocaine with adrenaline (5 microg ml(-1)) titrated to T6 block height before commencing general anesthesia. The postoperative analgesia regimen was 2 mg of intravenous morphine every 10 minutes for the first 48 hr and 1 gm of oral acetaminophen every 4-6 hr after initiation of oral diet at 24-48 hr as required. Morphine consumption, acetaminophen, pain scores, and side effects were recorded thoughout 48 hr after surgery. The results show patients in the clonidine and placebo groups were not different in terms of local anesthetics dose (p = 0.27), total morphine and acetaminophen requirement (p = 0.34, p = 0.1) respectively. Pain scores at rest and movement were also not different in both groups (p = 0.83, p = 0.64) respectively. No serious adverse effects were noted. The authors concluded that oral clonidine approximately 6 microg kg(-1) does not enhance the analgesic effect of epidural morphine 2 mg after hysterectomy.

The Journal of the American Osteopathic Association 2005; 105(6):273-9

CONTEXT: Administration of opioids for treatment of pain after total abdominal hysterectomy (TAH) is a common postoperative procedure, providing an excellent parameter for evaluating the efficacy of postsurgical osteopathic manipulative treatment (OMT). OBJECTIVE: To determine whether a combination of preemptive morphine sulfate and postoperative OMT could provide improved analgesic effects. DESIGN: Randomized double-blind controlled trial. SETTING AND PATIENTS: Thirty-nine hospitalized patients assigned to one of four treatment groups: (1) preoperative saline and postoperative sham manipulative treatment; (2) preoperative saline and postoperative OMT; (3) preoperative morphine and postoperative sham manipulative treatment; or (4), preoperative morphine and postoperative OMT. INTERVENTION: Saline (control) or morphine, 10 mg, delivered intravenously (IV) 10 minutes before surgical incision. All patients received a postoperative patient-controlled IV analgesia pump containing morphine. At specified intervals following preoperative IV injections, blood was drawn and analyzed for morphine concentrations. Subjects were also asked to rate their postoperative levels of pain, nausea, and vomiting. RESULTS: There were no differences in either pain, or nausea and vomiting scores among the four study groups. Patients in Group 4 used less morphine than those in the Group 3 for the first 24 hours (P=.02) and from 25-48 hours (P=.01) after elective TAH. Morphine blood concentrations were lower after 24 hours in Group 4 compared with Group 2 (P=.04). CONCLUSION: Administration of postoperative OMT enhanced pre- and postoperative morphine analgesia in the immediate 48-hour period following elective TAH, demonstrating that OMT can be a therapeutic adjunct in pain management following this procedure.

Kocabas et al 2005

The use of tramadol and morphine for pain relief after abdominal hysterectomy

Kocabas S, Karaman S, Uysallar E, Firat V.

Clinical and experimental obstetrics & gynecology 2005;32(1):45-8

OBJECTIVE: The aim of this study was to determine whether the addition of a tramadol infusion to morphine patient-controlled analgesia (PCA) results in improved analgesic efficacy compared with morphine PCA alone after abdominal hysterectomy. METHODS: Sixty patients undergoing abdominal hysterectomy were randomized into two groups, each receiving IV morphine PCA after surgery. The tramadol group received a loading dose of tramadol (1 mg/kg) at skin closure and a postoperative infusion of tramadol at 0.2 mg/kg/h. The control group received an equivalent volume of saline at skin closure and a postoperative saline infusion. RESULTS: The addition of a tramadol infusion to morphine PCA was associated with lower pain scores, a reduction in PCA morphine requirements (27 +/- 4.6 mg vs 40.5 +/- 5.4 mg over 24 h) and improved patient satisfaction with pain relief (p < 0.05). No intergroup differences were found with regard to sedation, nausea and antiemetic use (p > 0.05). CONCLUSION: The addition of a tramadol infusion to morphine PCA resulted in improved analgesic efficacy and reduced morphine requirements compared with morphine PCA alone after abdominal hysterectomy.

Intrathecal opioids provide postoperative analgesia and hemodynamic stability by depressing the neuroendocrine response during the perioperative period. The effects of preoperative intrathecal morphine on perioperative hemodynamics, stress response, and postoperative analgesia were evaluated in patients undergoing abdominal hysterectomy with general anesthesia. A total of 24 patients were randomly assigned to the morphine group (n=12) or the control group (n=12). Patients in the morphine group were given intrathecal 5 microg/kg(-1) morphine before surgery. In all patients, general anesthesia was induced with 1 g/kg(-1) remifentanil, 2 mg/kg(-1) propofol, and 0.1 mg/kg(-1) vecuronium and was maintained with 1% to 2% sevoflurane-35% oxygen in N2O and remifentanil infusion. All patients received intravenous morphine patient-controlled analgesia after surgery. Postoperative pain was evaluated by means of a visual analogue scale. Blood samples were taken at 4 time points before and up to 4 hours after the start of surgery for assessment of plasma epinephrine, norepinephrine, and glucose. Mean arterial pressure (MAP), heart rate (HR), and adverse effects were recorded. Intraoperative hemodynamics was similar in both groups, but postoperative HR and MAP values at 4 h, 8 h, 12 h, and 20 h were significantly lower in the morphine group (P<.05). Postoperative VAS scores, total morphine consumption, and plasma epinephrine, norepinephrine, and glucose levels were significantly lower in the morphine group than in the control group (P<.05). Preoperative intrathecal morphine enhanced the quality of postoperative analgesia, decreased morphine consumption, and depressed the systemic stress response in patients undergoing total abdominal hysterectomy with general anesthesia

Sharma et al 2006

Efficacy of intrathecal adenosine for postoperative pain relief

Sharma M, Mohta M, Chawla R

European Journal of Anaesthesiology 2006; 23(6):449-53

BACKGROUND AND OBJECTIVE: Adenosine, by intravenous and intrathecal routes, is known to alleviate various types of pain. However, the role of intrathecal adenosine in providing postoperative analgesia has not been confirmed. The aim of the present study was to evaluate the efficacy of intrathecal adenosine for postoperative pain relief, and to determine its role for pre-emptive analgesia. METHODS: Ninety ASA I and II females, undergoing elective abdominal hysterectomy, were randomly divided into three groups of 30 patients each. Patients in the 'early adenosine' group received intrathecal adenosine 1,000 microg, 30 min before induction of anaesthesia. Patients in the 'late adenosine' group received the same dose before reversal of neuromuscular blockade. Control patients did not receive any test drug. A balanced general anaesthesia technique was used in all patients. Pain intensity scores using a visual analogue scale, sedation scores, time to first rescue analgesic and total morphine requirement were recorded. RESULTS: There was no significant difference in pain intensity scores, sedation scores, total morphine requirements and time to first rescue analgesic among the three groups. CONCLUSION: Intrathecal adenosine 1,000 microg is not effective as an analgesic for postoperative pain relief, and there is no pre-emptive effect.

Lo et al 2005

Morphine sparing with droperidol in patient-controlled analgesi

Lo Y, Chia YY, Liu K, Ko NH

Journal of clinical anesthesia 2005;17(4):271-5

To determine if droperidol has a morphine-sparing effect when coadministered with morphine via patient-controlled analgesia (PCA) for postoperative pain management. DESIGN: A randomized, double-blind clinical study. SETTING: Department of Anesthesiology, Kaohsiung Veterans General Hospital, Taiwan. PATIENTS: One hundred seventy-nine American Society of Anesthesiologists physical status 1 and 2 female patients undergoing abdominal hysterectomy. INTERVENTIONS: At the end of surgery, patients in the droperidol group received PCA, with the device programmed to deliver a bolus dose of 1 mg morphine and 50 mug droperidol on demand. Patients in the control group received 1 mg morphine on demand. For both groups, PCA lockout was 5 minutes between boluses, with a 4-hour morphine limit of 30 mg. MEASUREMENTS AND MAIN RESULTS: Pain intensity at rest or on movement and relative sedation score were evaluated and recorded at 6, 12, 24, 48, and 72 hours after surgery. Related side effects were also evaluated and recorded on postoperative days 1, 2, and 3. Morphine use was significantly lower for the droperidol group than the control group during the postoperative 72-hour period (33.9 + /- 9.8 and 54.9 +/- 12.1 mg, respectively), with significantly decreased pain intensity levels for the former relative to the latter at 48 hours (pain intensity on movement: 3.9 +/- 1.2 vs 4.3 +/- 0.9, respectively; P = .049) and 72 hours (pain intensity on movement: 3.0 +/- 1.1 vs 3.6 +/- 0.5, respectively; P = .003; pain intensity at rest: 1.3 +/- 1.0 vs 1.6 +/- 0.7, respectively; P = .033) subsequent to surgery. Control subjects demonstrated a greater frequency of postoperative nausea and vomiting than did their droperidol counterparts on postoperative day 1. CONCLUSION: Coadministration of 50 mug droperidol and 1 mg morphine on demand via PCA provides a morphine-sparing effect and reduces the frequency of postoperative nausea and vomiting.

BACKGROUND: This study was designed to examine the analgesic and dose- related antiemetic efficacy of diphenhydramine-morphine mixture for intravenous patient-controlled analgesia (PCA). METHODS: Healthy women, undergoing abdominal total hysterectomy were recruited to this double-blinded randomized placebo-controlled study. Patients were randomly allocated to one of three groups (n=40 each). In group 1, patients received saline at induction and morphine 1 mg ml(-1) alone for postoperative PCA. Patients in groups 2 and 3 received diphenhydramine 30 mg i.v. at induction and were given a 1.2:1 or a 4.8:1 ratio, respectively, of diphenhydramine-morphine mixture for postoperative PCA. RESULTS: A total of 112 patients completed the study. The incidence of postoperative nausea (31.6% vs 67.6%, P<0.01) and vomiting (15.8% vs 40.5%, <0.05) was significantly lower in group 3 than in group 1. Furthermore, the incidence of severe nausea was significantly lower in group 3 than in group 1 (2.6% vs 24.3%, P<0.05) . The rescue antiemetic requirements were also significantly less in group 3 than in group 1 (5.3% vs 24.3%, P<0.05). However, there was no significant difference between group 2 and group 1 in any of the comparisons. Pain intensity, 24-h morphine consumption and diphenhydramine-related side-effects, such as sedation or dry mouth, did not differ among the three groups. CONCLUSION: An initial bolus of diphenhydramine 30 mg at anaesthetic induction followed by postoperative PCA with a 4.8:1, but not 1.2:1, diphenhydramine- morphine mixture provides an effective antiemetic efficacy without morphine-sparing effects

Chia et al 2004

Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy

Chia YY, Chan MH, Ko NH, Liu K

British journal of anaesthesia 2004;93(6):799-805

BACKGROUND: Perioperative use of beta-blockers has been advocated as a strategy to prevent cardiac sequelae. This study evaluated the influence of perioperative esmolol administration upon anaesthesia and postoperative pain management amongst patients undergoing hysterectomy. METHODS: Ninety-seven ASA I-II patients, undergoing abdominal total hysterectomy, were randomly divided into one of two groups. Patients in the Esmolol group received an i.v. loading dose of esmolol 0.5 mg kg(-1) followed by infusion of 0.05 mg kg(-1) min(-1) before anaesthesia induction. The infusion was documented at the completion of surgery. The Control group received a volume of normal saline. After surgery, all patients were treated with patient- controlled i.v. analgesia (PCA), which was programmed to deliver 1 mg of morphine on demand for 3 consecutive days. Pain intensity on movement and at rest, sedation score, and side effects were recorded. RESULTS: The two groups were comparable with respect to their characteristics. Patients in the esmolol group received significantly lower end-tidal isoflurane concentrations (1.0 (0.3) vs 1.4 (0.5)%, respectively; P<0.001) and fentanyl (0.9 (0.2) vs 1.2 (0.5) microg kg (-1), respectively; P=0.006) during anaesthesia. They also showed a reduced heart rate and arterial pressure response to tracheal intubation, skin incision, and tracheal extubation. The Esmolol group consumed less PCA morphine in 3 days (37.3 (8.4) vs 54.7 (11.2) mg, respectively; P=0.005). Pain intensity and medication side effects were similar in the two groups. CONCLUSION: The results suggest that perioperative esmolol administration during anaesthesia reduces the intraoperative use of inhalation anaesthetic and fentanyl, decreases haemodynamic responses, and reduced morphine consumption for the first 3 postoperative days.

Background: The aim of our study was to assess the effect of intraperitoneal and abdominal wall infiltration with bupivacaine plus tramadol and tenoxicam after total abdominal hysterectomy. Methods: Sixty patients who have undergone abdominal hysterectomy were allocated randomly to three different groups: group I (bupivacaine + tramadol): 20 patients infiltrated with 40 ml 0.25% bupivacaine plus 100 mg tramadol; group II (bupivacaine + tenoxicam): 20 patients infiltrated with 40 ml 0.25% bupivacaine plus 20 mg tenoxicam; and group III (bupivacaine + tramadol + tenoxicam): 20 patients infiltrated with 40 ml 0.25% bupivacaine + 100 mg tramadol + 20 mg tenoxicam. The intraperitoneal and abdominal wall infiltration was done to each patient after hysterectomy. The study was performed in a double-blind controlled manner. Results: In group III, pain scores (VAS) and analgesic requirement (tramadol) during the 24 h after surgery were significantly lower than in groups I and II. Tramadol requirements after the operation were similar in groups I and II. Pain scores, were similar in groups I and II. Side effects and recovery variables were similar in all groups.

De Castro et al 2005

BACKGROUND AND OBJECTIVES: This study investigates the ability of epidural S(+)ketamine, NMDA receptor antagonist, plus local anesthetic (bupivacaine) injection to promote preemptive analgesia in patients undergoing total abdominal hysterectomy, when this solution is administered before surgical incision. METHODS: Participated in this prospective double-blind study 30 patients were randomly assigned in two equal groups. Epidural injection and catheter insertion were performed at L(1)-L(2) interspace. Group 1 (G1) patients received 17 m L bupivacaine 0.25% plus 3 mL S(+)ketamine (30 mg), 30 min before surgical incision, followed by 20 mL saline 30 min after incision. Group 2 (G2) patients received 20 mL saline 30 min before surgical incision, followed by 17 mL bupivacaine 0.25% plus 3 mL S(+)ketamine (30 mg) 30 min after incision. General anesthesia was induced with propofol, pancuronium, O(2) and isoflurane. Postoperative analgesia consisted of epidural fentanyl plus bupivacaine bolus with 4h minimal interval. If necessary, IV dipyrone supplementation was administered. Patients were evaluated for analgesia by a verbal and numeric scale (at recovery and every six hours until 24 postoperative hours). Time to first analgesic request and total analgesic requirements were recorded. RESULTS: There were no significant differences between groups in time to first analgesic request, total analgesic consumption and numeric or verbal scale pain scores. CONCLUSIONS: This study failed to demonstrate a preemptive effect of epidural administration of bupivacaine and S(+)ketamine in the doses tested for abdominal hysterectomy

OBJECTIVES: To test the null hypothesis of no significant difference between laparoscopic hysterectomy (LH), abdominal hysterectomy (AH) and vaginal hysterectomy (VH) with regard to each of the outcome measures of the trial, and also to assess the cost-effectiveness of the alternatives. DESIGN: Patients were allocated to either the vaginal or abdominal trial by the individual surgeon according to their usual clinical practice. After allocation patients were then randomised to receive either LH or the default procedure in an unbalanced 2:1 manner. SETTING: Forty-three surgeons from 28 centres throughout the UK and two centres in South Africa took part in the study. PARTICIPANTS: Patients with gynaecological symptoms that, in the opinion of the gynaecologist and the patient, justified hysterectomy. INTERVENTIONS: Of 1380 patients recruited to the study, 876 were included in the AH trial and 504 in the VH trial. In the AH trial, 584 patients had a laparoscopic type of hysterectomy (designated ALH) and 292 had a standard AH. In the VH trial 336 had a VLH and 168 had a standard VH. A cost--utility analysis was undertaken based on a 1-year time horizon. Quality-adjusted life years (QALYs) were estimated using the EQ-5D. RESULTS: Compared with AH, LH was associated with a higher rate of major complications, less postoperative pain and shorter hospital stay, but took longer to perform. Securing the ovarian pedicles with laparoscopic sutures was used in only 7% of cases but was associated with 25% of the complications. At the 6 weeks postoperative point, ALH was associated with a significantly better physical component of the SF-12 (QoL questionnaire), better body image scale scores and a significantly increased frequency of sexual intercourse than AH. These differences were not observed at either 4 or 12 months after surgery. There were no significant differences in any measured outcome between LH and VH except that VLH took longer to perform and was associated with a higher rate of detecting unexpected pathology. Compared with VH, VLH had a higher mean cost per patient of GBP401 and higher mean QALYs of 0.0015, resulting in an incremental cost per QALY gained of GBP267,333. The probability that VLH is cost-effective was less than 50% for a large range of willingness to pay values for an additional QALY. Compared with AH, ALH had a higher mean cost per patient of GBP186 and higher mean QALYs of 0.007, resulting in an incremental cost per QALY gained of GBP26,571. CONCLUSIONS: ALH is associated with a significantly higher risk of major complications and takes longer to perform than AH. ALH is, however, associated with less pain, quicker recovery and better short-term QoL after surgery than AH. The cost-effectiveness of ALH is finely balanced and is also influenced by the choice of reusable versus disposable equipment. Individual surgeons must decide between patient-orientated benefits and the risk of severe complications. VLH was not cost-effective relative to VH. Recommendations for future research include the application and relevance of QoL measures following hysterectomy, and long-term follow-up; patient preferences; reducing complication rates; improving gynaecological surgical training; surgeon effect in surgery trials; care pathways for hysterectomy; additional pathology identification in LH and meta-analysis/further trial of VH versus LH.